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Full issue
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open
access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.
It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and also
more traditional review articles (“deep insights”) on the above subjects and on surrounding topics.
It also present case reports in hematology and educational items in the various related topics for students in Medicine
and in Sciences.
Editorial correspondance
Jean-Loup Huret
Genetics, Department of Medical Information,
University Hospital
F-86021 Poitiers, France
tel +33 5 49 44 45 46 or +33 5 49 45 47 67
[email protected] or [email protected]
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a
non profit organisation.
Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy
Institute – Villejuif – France).
http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open
access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.
It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and also
more traditional review articles (“deep insights”) on the above subjects and on surrounding topics.
It also present case reports in hematology and educational items in the various related topics for students in Medicine
and in Sciences.
Editorial correspondance
Jean-Loup Huret
Genetics, Department of Medical Information,
University Hospital
F-86021 Poitiers, France
tel +33 5 49 44 45 46 or +33 5 49 45 47 67
[email protected] or [email protected]
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a
non profit organisation.
Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy
Institute – Villejuif – France).
http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the
Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research
(CNRS) on its electronic publishing platform I-Revues.
Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Editor
Jean-Loup Huret
(Poitiers, France)
Volume 4, Number 4, October - December 2000
Table of contents
Gene Section
IKZF1 (Ikaros family zinc finger 1)
Jean-Loup Huret
179
MYC (v-myc myelocytomatosis viral oncogene homolog (avian))
Niels B Atkin
181
PIM1 (pim-1 oncogene)
Jean-Loup Huret
183
TFF1 (trefoil factor 1)
Catherine Tomasetto, Marie-Christine Rio
185
TRAF4 (TNF receptor-associated factor 4)
Catherine H Régnier, Catherine Tomasetto, Marie-Christine Rio
186
BLM (Bloom)
Mounira Amor-Guéret
188
TAF15 (TAF15 TAF15 RNA polymerase II, TATA box
binding protein (TBP)-associated factor, 68kDa)
Jean-Loup Huret
190
PRDX1 (peroxiredoxin 1)
Maité P Prosperi, Didier Ferbus, Gérard Goubin
192
PML (Promyelocytic leukemia)
Franck Viguié
193
RARA (Retinoic acid receptor, alpha)
Franck Viguié
195
ZNF146 (zinc finger protein 146)
Gérard Goubin
197
Leukaemia Section
Fibrogenesis imperfecta ossium
Daniel Bontoux, Michel Alcalay, Jean-Loup Huret
198
Chronic myelogenous leukaemia (CML)
Ali G Turhan
200
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Hairy Cell Leukemia (HCL) and Hairy Cell Leukemia Variant (HCL-V)
Vasantha Brito-Babapulle, Estella Matutes, Daniel Catovsky
203
t(9;22)(q34;q11) in CML
Ali G Turhan
205
Solid Tumour Section
Thyroid: Papillary carcinoma
Marco A Pierotti
209
Bladder: transitional cell carcinoma
Jean-Loup Huret, Claude Léonard
212
Cancer Prone Disease Section
Bloom syndrome
Mounira Amor-Guéret
218
Simpson-Golabi-Behmel syndrome
Hope H Punnett
221
Cockayne syndrome
Claude Viguié
222
Trichothiodystrophy (TTD)
Claude Viguié
223
Werner syndrome
Mounira Amor-Guéret
224
Xeroderma pigmentosum
Claude Viguié
226
Deep Insight Section
Micronuclei : Pitfalls and Problems
John RK Savage
229
Educational Items Section
Cancer Prone Diseases
Jean-Loup Huret
234
Embryology, Semiology, Dysmorphology
Jean-Loup Huret
237
Trisomy 21
Jean-Loup Huret, Pierre-Marie Sinet
244
Other Constitutional Chromosome Diseases
Jean-Loup Huret, Claude Léonard
248
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
IKZF1 (Ikaros family zinc finger 1)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: August 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/IkarosID258.html
DOI: 10.4267/2042/37660
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Implicated in
HGNC (Hugo): IKZF1
Other names: IK1; LYF1; ZNFN1A1 (zinc finger
protein, subfamily 1A, 1)
Location: 7p12
t(3;7)(q27;p12) diffuse large B-cell
lymphoma (DLCL) --> BCL6 / Ikaros
Note
Only 2 cases to date.
Hybrid/Mutated gene
5' Ikaros - 3' BCL6 fusion transcript; it is supposed that
substitution of the promoter of BCL6 may be
responsible for BCL6 deregulation.
DNA/RNA
Transcription
3629 bp mRNA; coding sequence: 1559 bp; 6 different
splicings (--> 6 isoform proteins: ik1-ik6).
References
Protein
Brown KE, Guest SS, Smale ST, Hahm K, Merkenschlager M,
Fisher AG. Association of transcriptionally silent genes with
Ikaros complexes at centromeric heterochromatin. Cell. 1997
Dec 12;91(6):845-54
Description
519 amino acids; 58 kDa; possesses 2 Zinc-finger
(C2H2-type) domains: one with 4 ZnF, the second with
2 ZnF; DNA binding.
Georgopoulos K, Winandy S, Avitahl N. The role of the Ikaros
gene in lymphocyte development and homeostasis. Annu Rev
Immunol. 1997;15:155-76
Expression
Nichogiannopoulou A, Trevisan M, Friedrich C, Georgopoulos
K. Ikaros in hemopoietic lineage determination and
homeostasis. Semin Immunol. 1998 Apr;10(2):119-25
Specificity for hematopoietic organs in the foetus and
in the adult as well.
Nichogiannopoulou A, Trevisan M, Neben S, Friedrich C,
Georgopoulos K. Defects in hemopoietic stem cell activity in
Ikaros mutant mice. J Exp Med. 1999 Nov 1;190(9):1201-14
Localisation
Nuclear.
Winandy S, Wu L, Wang JH, Georgopoulos K. Pre-T cell
receptor (TCR) and TCR-controlled checkpoints in T cell
differentiation are set by Ikaros. J Exp Med. 1999 Oct
18;190(8):1039-48
Function
Transcription regulator; can repress transcription
through the recruitment of histone deacetylase
complexes; role in conjunction with Aiolos;
hemopoietic-specific zinc finger protein regulator of B
and T-cell differentiation.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Yoshida S, Kaneita Y, Aoki Y, Seto M, Mori S, Moriyama M.
Identification of heterologous translocation partner genes fused
to the BCL6 gene in diffuse large B-cell lymphomas: 5'-RACE
and LA - PCR analyses of biopsy samples. Oncogene. 1999
Dec 23;18(56):7994-9
179
IKZF1 (Ikaros family zinc finger 1)
Huret JL
Hosokawa Y, Maeda Y, Ichinohasama R, Miura I, Taniwaki M,
Seto M. The Ikaros gene, a central regulator of lymphoid
differentiation, fuses to the BCL6 gene as a result of
t(3;7)(q27;p12) translocation in a patient with diffuse large Bcell lymphoma. Blood. 2000 Apr 15;95(8):2719-21
This article should be referenced as such:
Huret JL. IKZF1 (Ikaros family zinc finger 1). Atlas Genet
Cytogenet Oncol Haematol. 2000; 4(4):179-180.
Koipally J, Georgopoulos K. Ikaros interactions with CtBP
reveal a repression mechanism that is independent of histone
deacetylase activity. J Biol Chem. 2000 Jun 30;275(26):19594602
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
180
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
MYC (v-myc myelocytomatosis viral oncogene
homolog (avian))
Niels B Atkin
Department of Cancer Research, Mount Vernon Hospital, Northwood, Middlesex, UK (NBA)
Published in Atlas Database: August 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/MYCID27.html
DOI: 10.4267/2042/37661
This article is an update of : Larizza L, Beghini A. KIT. Atlas Genet Cytogenet Oncol Haematol 1999;3(1):1-3
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Other names: C-MYC. Identified as the oncogene of
the MC29 avian myelocytomatosis virus
HGNC (Hugo): MYC
Location: 8q24
Description
439 amino acids and 48 kDa in the p64; 454 amino
acids in the p67 (15 additional amino acids in N-term;
contains from N-term to C-term: a transactivation
domain,an acidic domain, a nuclear localization signal,
a basic domain, an helix-loop-helix motif, and a leucin
zipper; DNA binding protein.
Expression
Expressed in almost all proliferating cells in embryonic
and adult tissues; in adult tissues, expression correlates
with cell proliferation; abnormally high expression is
found in a wide variety of human and rodent tumours.
Localisation
Located predominantly in the nucleus.
Function
The encoded myc oncoproteins are apparently
transcription factors known as basic region-helixloophelix-leucine zipper (b-HLH-Zip) proteins; like other bHLH-Zip proteins, they modulate the expression of
target genes by binding to specific DNA sequences.
In this case, however, the binding requires dimerization
to another b-HLH-Zip protein, namely Max (the latter
can also form heterodimers with Mad as well as
homodimers with itself). Myc/Max complexes activate
transcription and promote cell proliferation and
transformation. Mad/Max complexes, however, repress
transcription
and
block
myc-mediated
cell
transformation. All three complexes bind to the same
DNA sequence and are competitors.
c-MYC (8q24) in normal cells: PAC 944B18 (top) and PAC
968N11 (below) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics.
DNA/RNA
Transcription
Alternative splicing; coding sequences: 1318 and 1362
bp for proteins p64 and p67 respectively.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
181
MYC (v-myc myelocytomatosis viral oncogene homolog (avian))
Atkin NB
In adult respiratory distress syndrome the degree of
diffuse alveolar damage and consequently the
prognosis may be related to the intensity of expression
of c-myc in the alveolar cells which, if severe, may
contribute to deregulation of cellular proliferation and
apoptosis. In endometriosis, c-myc expression is a
possibly important regulator of cellular proliferation.
Expression of c-myc is required for proliferation; it can
over-ride p53-induced Gl-arrest by inducing an
inhibitor of the cyclin kinase inhibitor WAFI(p2l). The
latter (located at 6p2l) normally coordinates S and M
phases of the cell cycle. If absent, cells with damaged
DNA arrest not in GI but in a G2-like state from which
they can pass through additional S phases without
intervening normal mitoses (the deformed polyploid
cells that result may then die by apoptosis). The
uncoupling of S and M may contribute to the
acquisition of the chromosomal abnormalities
manifested by most tumour cells when apoptotic
pathways have been circumvented.
To be noted
Note
Although c-myc appears to be active in variety of
tumours, it is important to realise that in common with
other mechanistic pathways to cancer induction and
progression no single genetic event (including c-myc
deregulation) will prove to be necessary in the light of
the inherent complexity and diversity of cellular
pathways leading to neoplasia.
Homology
The human myc family also includes N-myc and Lmyc, rather specifically implicated in neuroblastoma
and small-cell lung carcinoma, respectively, in which
amplified copy numbers have been found.
References
Implicated in
Rappold GA, Hameister H, Cremer T, Adolph S, Henglein B,
Freese UK, Lenoire GM, Bornkamm GW. c-myc and
immunoglobulin kappa light chain constant genes are on the
8q+ chromosome of three Burkitt lymphoma lines with t(2;8)
translocations. EMBO J. 1984 Dec 1;3(12):2951-5
Burkitt's lymphoma
Hybrid/Mutated gene
The gene is activated by translocation next to an
immunoglobulin constant gene. Most frequently, it is
positioned near the immunoglobulin heavy-chain (IgH)
constant region on chromosome 14 but, in some
tumours, near the light-chain region chromosome 2
(IgK) or 22 (IgL). It is now known that
immunoglobulin joining enzymes may be involved in
recombinations associated with a variety of
chromosomal translocations in B and T cells.
Amplification has been described in many types
of tumour, including breast, cervical and colon
cancers, as well as in squamous cell
carcinomas of the head and neck, myeloma,
non-Hodgkin's lymphoma, gastric
adenocarcinomas and ovarian cancer
Prognosis
C-myc involvement is by no means universally found
in these cancers; there may be a correlation with the
more advanced stages, suggesting a value as a
prognostic indicator (although this has not been
demonstrated in some studies for breast, ovarian and
cervical cancers).
Oncogenesis
C-myc gene activation (enhanced expression and/or
amplification) may result from chromosomal
duplication as well as translocation, and from retroviral
as well as point mutation. Multiple copies of the gene
may be evidenced in homogeneously staining
chromosomal regions and in double minutes.
Saksela K, Bergh J, Lehto VP, Nilsson K, Alitalo K.
Amplification of the c-myc oncogene in a subpopulation of
human small cell lung cancer. Cancer Res. 1985
Apr;45(4):1823-7
Depinho RA, Hatton K, Ferrier P, Zimmerman K, Legouy E,
Tesfaye A, Collum R, Yancopoulos G, Nisen P, Alt F. Myc
family genes: a dispersed multi-gene family. Ann Clin Res.
1986;18(5-6):284-9
Schenken RS, Johnson JV, Riehl RM. c-myc protooncogene
polypeptide expression in endometriosis. Am J Obstet
Gynecol. 1991 Apr;164(4):1031-6; discussion 1036-7
Garte SJ. The c-myc oncogene in tumor progression. Crit Rev
Oncog. 1993;4(4):435-49
Roschke V, Kopantzev E, Dertzbaugh M, Rudikoff S.
Chromosomal translocations deregulating c-myc
are
associated with normal immune responses. Oncogene. 1997
Jun 26;14(25):3011-6
Schreiber-Agus N, DePinho RA. Repression by the Mad(Mxi1)Sin3 complex. Bioessays. 1998 Oct;20(10):808-18
Adamson A, Perkins S, Brambilla E, Tripp S, Holden J, Travis
W, Guinee D Jr. Proliferation, C-myc, and cyclin D1 expression
in diffuse alveolar damage: potential roles in pathogenesis and
implications for prognosis. Hum Pathol. 1999 Sep;30(9):1050-7
Nesbit CE, Tersak JM, Prochownik EV. MYC oncogenes and
human
neoplastic
disease.
Oncogene.
1999
May
13;18(19):3004-16
Ozkara HA, Ozkara S, Topçu S, Criss WE. Amplification of the
c-myc oncogene in non-small cell lung cancer. Tumori. 1999
Nov-Dec;85(6):508-11
This article should be referenced as such:
Role of c-myc in other conditions
Atkin NB. MYC (v-myc myelocytomatosis viral oncogene
homolog (avian)). Atlas Genet Cytogenet Oncol Haematol.
2000; 4(4):181-182.
Disease
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
182
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
PIM1 (pim-1 oncogene)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: August 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/PIM1ID261.html
DOI: 10.4267/2042/37662
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
HGNC (Hugo): PIM1
Location: 6p21.2
Hybrid/Mutated gene
5' PIM1 - 3' BCL6 fusion transcript; it is supposed that
substitution of the promoter of BCL6 may be
responsible for BCL6 deregulation.
DNA/RNA
References
Identity
Selten G, Cuypers HT, Boelens W, Robanus-Maandag E,
Verbeek J, Domen J, van Beveren C, Berns A. The primary
structure of the putative oncogene pim-1 shows extensive
homology with protein kinases. Cell. 1986 Aug 15;46(4):603-11
Description
5 kb of genomic DNA; 6 exons.
Transcription
Meeker TC, Nagarajan L, ar-Rushdi A, Croce CM. Cloning and
characterization of the human PIM-1 gene: a putative
oncogene related to the protein kinases. J Cell Biochem. 1987
Oct;35(2):105-12
2.6 kb mRNA; coding sequence 941 bp.
Protein
Mochizuki T, Kitanaka C, Noguchi K, Sugiyama A, Kagaya S,
Chi S, Asai A, Kuchino Y. Pim-1 kinase stimulates c-Mycmediated death signaling upstream of caspase-3 (CPP32)-like
protease activation. Oncogene. 1997 Sep 18;15(12):1471-80
Description
313 amino acids, 36 kDa; protein kinase domain, ATPbinding site.
Leverson JD, Koskinen PJ, Orrico FC, Rainio EM, Jalkanen
KJ, Dash AB, Eisenman RN, Ness SA. Pim-1 kinase and p100
cooperate to enhance c-Myb activity. Mol Cell. 1998
Oct;2(4):417-25
Expression
Plays a role in signal transduction in blood cells.
Function
Mochizuki T, Kitanaka C, Noguchi K, Muramatsu T, Asai A,
Kuchino Y. Physical and functional interactions between Pim-1
kinase and Cdc25A phosphatase. Implications for the Pim-1mediated activation of the c-Myc signaling pathway. J Biol
Chem. 1999 Jun 25;274(26):18659-66
Serine/threonine-protein
kinase;
regulated
by
hematopoietic cytokine receptors; synergy with c-MYC
in cell proliferation and in apoptosis induction (through
an enhancement of the activation of caspase-3 -like
proteases; Cdc25A (cell cycle phosphatase) is a
substrate for Pim-1.
Shirogane T, Fukada T, Muller JM, Shima DT, Hibi M, Hirano
T. Synergistic roles for Pim-1 and c-Myc in STAT3-mediated
cell cycle progression and antiapoptosis. Immunity. 1999
Dec;11(6):709-19
Implicated in
Yoshida S, Kaneita Y, Aoki Y, Seto M, Mori S, Moriyama M.
Identification of heterologous translocation partner genes fused
to the BCL6 gene in diffuse large B-cell lymphomas: 5'-RACE
and LA - PCR analyses of biopsy samples. Oncogene. 1999
Dec 23;18(56):7994-9
t(3;6)(q27;p21.2) diffuse large B-cell
lymphoma (DLCL) --> BCL6 / PIM1
Note
Only 1 case to date.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
183
PIM1 pim-1 oncogene
Huret JL
Koike N, Maita H, Taira T, Ariga H, Iguchi-Ariga SM.
Identification of heterochromatin protein 1 (HP1) as a
phosphorylation target by Pim-1 kinase and the effect of
phosphorylation on the transcriptional repression function of
HP1(1). FEBS Lett. 2000 Feb 4;467(1):17-21
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
This article should be referenced as such:
Huret JL. PIM1 (pim-1 oncogene). Atlas Genet Cytogenet
Oncol Haematol. 2000; 4(4):183-184.
184
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Short Communication
TFF1 (trefoil factor 1)
Catherine Tomasetto, Marie-Christine Rio
I.G.B.M.C., BP163, 1 rue Laurent Fries, 67404 ILLKIRCH, France (CT, MCR)
Published in Atlas Database: August 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/TFF1ID201.html
DOI: 10.4267/2042/37663
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Implicated in
Other names: pS2
HGNC (Hugo): TFF1
Location: 21q22.3
Local order: Belongs to the TFF cluster.
Disease
Overexpressed
in
estradiol-dependent
breast
carcinomas; overexpressed in carcinoma of several
other organs; loss of expression in half of gastric
carcinomas (TFF1 is normally expressed in the
stomach).
Prognosis
Good prognosis factor, and marker of response to
hormonal treatment in breast carcinomas.
DNA/RNA
Description
5kb gene; 3 exons.
References
Transcription
600bp cDNA; coding sequence: 252 bp.
Foekens JA, Rio MC, Seguin P, van Putten WL, Fauque J,
Nap M, Klijn JG, Chambon P. Prediction of relapse and
survival in breast cancer patients by pS2 protein status.
Cancer Res. 1990 Jul 1;50(13):3832-7
Protein
Description
Lefebvre O, Wolf C, Kédinger M, Chenard MP, Tomasetto C,
Chambon P, Rio MC. The mouse one P-domain (pS2) and two
P-domain (mSP) genes exhibit distinct patterns of expression.
J Cell Biol. 1993 Jul;122(1):191-8
84 amino acids, containing a peptide signal; the 60 AAlong mature secreted peptide contains one TFF (TreFoil
Factor) domain and one acidic C-terminal domain.
Spyratos F, Andrieu C, Hacène K, Chambon P, Rio MC. pS2
and response to adjuvant hormone therapy in primary breast
cancer. Br J Cancer. 1994 Feb;69(2):394-7
Expression
Epithelial cells of the stomach surface.
Lefebvre O, Chenard MP, Masson R, Linares J, Dierich A,
LeMeur M, Wendling C, Tomasetto C, Chambon P, Rio MC.
Gastric mucosa abnormalities and tumorigenesis in mice
lacking the pS2 trefoil protein. Science. 1996 Oct
11;274(5285):259-62
Localisation
Cytoplasmic.
Function
In the maintenance of mucosa integrity; unknown at the
molecular level; deficient mice develop antro-pyloric
adenoma.
Ribieras S, Tomasetto C, Rio MC. The pS2/TFF1 trefoil factor,
from basic research to clinical applications. Biochim Biophys
Acta. 1998 Aug 19;1378(1):F61-77
Homology
Tomasetto C, Masson R, Linares JL, Wendling C, Lefebvre O,
Chenard MP, Rio MC. pS2/TFF1 interacts directly with the
VWFC cysteine-rich domains of mucins. Gastroenterology.
2000 Jan;118(1):70-80
TFF2/SP (spasmolytic
(intestinal trefoil factor).
peptide)
and
TFF3/ITF
This article should be referenced as such:
Tomasetto C, Rio MC. TFF1 (trefoil factor 1). Atlas Genet
Cytogenet Oncol Haematol. 2000; 4(4):185.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
185
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
TRAF4 (TNF receptor-associated factor 4)
Catherine H Régnier, Catherine Tomasetto, Marie-Christine Rio
I.G.B.M.C., BP163, 1 rue Laurent Fries, 67404 ILLKIRCH, France (CHR, CT, MCR)
Published in Atlas Database: August 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/TRAF4ID204.html
DOI: 10.4267/2042/37664
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Zinc-binding domains (3 CART domains) and a
carboxyl-terminal TRAF domain.
Other names: MLN62; CART1
HGNC (Hugo): TRAF4
Location: 17q11-q12
Local order: TRAF4, Lasp1(alias MLN50), c-erbB2,
MLN64, MLN51.
Expression
Epithelial cells; weak ubiquitous expression in adult
tissues; stronger expression level in kidney and thymus.
Localisation
Cytoplasmic; nuclear when overexpressed.
Function
Putative signal transducer.
Homology
To TRAF proteins (Tumor Necrosis Factor Receptor
Associated Factor).
Implicated in
17q11-q12 gene amplification; found in about
25% of primary breast carcinomas
Prognosis
Poor clinical outcome; increase risk of relapse.
TRAF4 (17q11-q12) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics.
References
DNA/RNA
Régnier CH, Tomasetto C, Moog-Lutz C, Chenard MP,
Wendling C, Basset P, Rio MC. Presence of a new conserved
domain in CART1, a novel member of the tumor necrosis
factor receptor-associated protein family, which is expressed in
breast carcinoma. J Biol Chem. 1995 Oct 27;270(43):25715-21
Description
5,5 kb gene; 7 exons.
Transcription
Tomasetto C, Régnier C, Moog-Lutz C, Mattei MG, Chenard
MP, Lidereau R, Basset P, Rio MC. Identification of four novel
human genes amplified and overexpressed in breast
carcinoma and localized to the q11-q21.3 region of
chromosome 17. Genomics. 1995 Aug 10;28(3):367-76
2 kb cDNA; coding sequence: 1410 bp.
Protein
Bièche I, Tomasetto C, Régnier CH, Moog-Lutz C, Rio MC,
Lidereau R. Two distinct amplified regions at 17q11-q21
involved in human primary breast cancer. Cancer Res. 1996
Sep 1;56(17):3886-90
Description
470 amino acids; 53 kDa; contains an amino-terminal
RING finger domain, a central stretch of six putative
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
186
TRAF4 TNF receptor-associated factor 4
Régnier CH, et al.
Arch RH, Gedrich RW, Thompson CB. Tumor necrosis factor
receptor-associated factors (TRAFs)--a family of adapter
proteins that regulates life and death. Genes Dev. 1998 Sep
15;12(18):2821-30
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
This article should be referenced as such:
Régnier CH, Tomasetto C, Rio MC. TRAF4 (TNF receptorassociated factor 4). Atlas Genet Cytogenet Oncol Haematol.
2000; 4(4):186-187.
187
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
BLM (Bloom)
Mounira Amor-Guéret
Institut Curie - Section de Recherche, UMR 2027 CNRS, Batiment 110, Centre Universitaire, F-91405 Orsay
Cedex, France (MAG)
Published in Atlas Database: September 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/BLM109.html
DOI: 10.4267/2042/37665
This article is an update of :
Amor-Guéret M. BLM (Bloom). Atlas Genet Cytogenet Oncol Haematol 2000;4(4):218
Huret JL. BLM (Bloom). Atlas Genet Cytogenet Oncol Haematol 1998;2(1):8
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Location: 15q26.1
the Werner syndrome gene, and the recently identified
human RecQL4, involved in the Rothmund-Thomson
syndrome, and RecQL5 proteins.
DNA/RNA
Mutations
Transcription
Germinal
4.4kb mRNA.
Five BLM mutations introducing amino acid
substitutions and four BLM mutations introducing
premature nonsense codons into the coding sequence
have been described to date; one BLM mutation
consisting in a 6 bp deletion accompanied by a 7 bp
insertion at nucleic acid position 2281 is common in
patients from Ashkenazi Jewish ancestry, leading to a
truncated protein of 739 amino acids in length; the
mutated BLM protein is totally or partially retained in
the cytoplasm, while the normal protein is nuclear.
Identity
Protein
Description
1417 amino acids; ATP binding in amino acid 689-696;
DEAH box in 795-798; two putative nuclear
localization signals in the C-term in 1334-1349.
Expression
Accumulates to high levels in S phase of the cell cycle,
persists in G2/M and sharply declines in G1.
Hyperphoshorylated in mitosis.
Implicated in
Bloom syndrome
Function
Disease
Bloom syndrome is a chromosome instability
syndrome/cancer prone disease (at risk of numerous,
early occurring cancers of various types).
Prognosis
1/3 of patients are dead at mean age 24 years, and the
mean age of the 2/3 remaining alive patients is 22
years.
Cytogenetics
Chromatid/chromosome
breaks;
triradial
and
quadriradial figures, highly elevated spontaneous sister
chromatid exchange rate.
3'-5'DNA helicase; probable role in DNA replication
and repair.
Participates in a supercomplex of BRCA1-associated
proteins named BASC (BRCA1-Associated genome
Surveillance Complex).
Recombinant protein promotes ATP-dependent branch
migration of Holliday junctions.
Homology
Homologous to RecQ helicases, a subfamily of DExH
box-containing helicases; in particular, similarity with
the four known human members in the RecQ
subfamily, human RecQL, human Wrn, the product of
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
188
BLM (Bloom)
Amor-Guéret M
Karow JK, Chakraverty RK, Hickson ID. The Bloom's
syndrome gene product is a 3'-5' DNA helicase. J Biol Chem.
1997 Dec 5;272(49):30611-4
References
Puranam KL, Blackshear PJ. Cloning and characterization of
RECQL, a potential human homologue of the Escherichia coli
DNA helicase RecQ. J Biol Chem. 1994 Nov
25;269(47):29838-45
Kitao S, Ohsugi I, Ichikawa K, Goto M, Furuichi Y, Shimamoto
A. Cloning of two new human helicase genes of the RecQ
family: biological significance of multiple species in higher
eukaryotes. Genomics. 1998 Dec 15;54(3):443-52
Seki M, Miyazawa H, Tada S, Yanagisawa J, Yamaoka T,
Hoshino S, Ozawa K, Eki T, Nogami M, Okumura K. Molecular
cloning of cDNA encoding human DNA helicase Q1 which has
homology to Escherichia coli Rec Q helicase and localization
of the gene at chromosome 12p12. Nucleic Acids Res. 1994
Nov 11;22(22):4566-73
Barakat A, Ababou M, Onclercq R, Dutertre S, Chadli E, Hda
N, Benslimane A, Amor-Guéret M. Identification of a novel
BLM missense mutation (2706T>C) in a Moroccan patient with
Bloom's syndrome. Hum Mutat. 2000 Jun;15(6):584-5
Dutertre S, Ababou M, Onclercq R, Delic J, Chatton B, Jaulin
C, Amor-Guéret M. Cell cycle regulation of the endogenous
wild type Bloom's syndrome DNA helicase. Oncogene. 2000
May 25;19(23):2731-8
Ellis NA, Groden J, Ye TZ, Straughen J, Lennon DJ, Ciocci S,
Proytcheva M, German J. The Bloom's syndrome gene product
is homologous to RecQ helicases. Cell. 1995 Nov
17;83(4):655-66
Karow JK, Constantinou A, Li JL, West SC, Hickson ID. The
Bloom's syndrome gene product promotes branch migration of
holliday junctions. Proc Natl Acad Sci U S A. 2000 Jun
6;97(12):6504-8
Ellis NA, German J. Molecular genetics of Bloom's syndrome.
Hum Mol Genet. 1996;5 Spec No:1457-63
Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R,
Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J,
Schellenberg GD. Positional cloning of the Werner's syndrome
gene. Science. 1996 Apr 12;272(5259):258-62
Lindor NM, Furuichi Y, Kitao S, Shimamoto A, Arndt C, Jalal S.
Rothmund-Thomson syndrome due to RECQ4 helicase
mutations: report and clinical and molecular comparisons with
Bloom syndrome and Werner syndrome. Am J Med Genet.
2000 Jan 31;90(3):223-8
Foucault F, Vaury C, Barakat A, Thibout D, Planchon P, Jaulin
C, Praz F, Amor-Guéret M. Characterization of a new BLM
mutation associated with a topoisomerase II alpha defect in a
patient with Bloom's syndrome. Hum Mol Genet. 1997
Sep;6(9):1427-34
Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. BASC,
a super complex of BRCA1-associated proteins involved in the
recognition and repair of aberrant DNA structures. Genes Dev.
2000 Apr 15;14(8):927-39
Kaneko H, Orii KO, Matsui E, Shimozawa N, Fukao T,
Matsumoto T, Shimamoto A, Furuichi Y, Hayakawa S,
Kasahara K, Kondo N. BLM (the causative gene of Bloom
syndrome) protein translocation into the nucleus by a nuclear
localization signal. Biochem Biophys Res Commun. 1997 Nov
17;240(2):348-53
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
This article should be referenced as such:
Amor-Guéret M. BLM (Bloom). Atlas Genet Cytogenet Oncol
Haematol. 2000; 4(4):188-189.
189
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
TAF15 (TAF15 TAF15 RNA polymerase II, TATA box
binding protein (TBP)-associated factor, 68kDa)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: September 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/TAF2NID256.html
DOI: 10.4267/2042/37666
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
complex (PIC); TFIID is composed of a TATA-boxbinding protein (TBP) and a number of TBP-associated
factors (TAFIIS); contribute to the activation of
transcription.
Identity
Other names: TAFIIN; TAF2N (TATA box binding
protein (TBP)-associated factor, RNA polymerase II,
N); RBP56 (RNA binding protein 56); TAFII68
HGNC (Hugo): TAF15
Location: 17q11.1-q11.2
Homology
With EWSR1 and FUS.
Mutations
DNA/RNA
Somatic
Description
Overexpression of TAF2N-FLI-1 chimeras in NIH3T3
cells leads to oncogenic transformation.
Spans 37kb; 16 exons.
Transcription
Implicated in
2.2 bp mRNA; alternative splicing: two isoforms of
cDNAs consisting of 2144 and 2153 bp; coding
sequence 1778 bp.
Extraskeletal myxoid chondrosarcomas
with t(9;17)(q22;q11) --> 5 prime
TAF2N/3 prime TEC
Protein
Disease
A rare tumour: 2.3% of soft tissue sarcomas often
localized in deep soft tissues of the lower extremities.
Description
589 and 592 amino acid, 62 kDa ; comprises a N-term
ser, tyr, gln, gly -rich region, followed by a an RNA
binding domain and a Cys2/Cys2 finger motif, and
repeats in C-term.
References
Reese JC, Apone L, Walker SS, Griffin LA, Green MR. Yeast
TAFIIS in a multisubunit complex required for activated
transcription. Nature. 1994 Oct 6;371(6497):523-7
Expression
Wide; in the fetus and in the adult.
Morohoshi F, Arai K, Takahashi EI, Tanigami A, Ohki M.
Cloning and mapping of a human RBP56 gene encoding a
putative RNA binding protein similar to FUS/TLS and EWS
proteins. Genomics. 1996 Nov 15;38(1):51-7
Localisation
Nuclear.
Function
Morohoshi F, Ootsuka Y, Arai K, Ichikawa H, Mitani S,
Munakata N, Ohki M. Genomic structure of the human
RBP56/hTAFII68 and FUS/TLS genes. Gene. 1998 Oct
23;221(2):191-8
Single strand DNA/RNA binding protein; part of
theTFIID and RNA polymerase II complex of proteins
which assemble on the promoter to form a pre-initiation
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
190
TAF15 (TAF15 TAF15 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 68kDa)
Bertolotti A, Bell B, Tora L. The N-terminal domain of human
TAFII68 displays transactivation and oncogenic properties.
Oncogene. 1999 Dec 23;18(56):8000-10
extraskeletal myxoid chondrosarcoma. Cancer Res. 1999 Oct
15;59(20):5064-7
Green MR. TBP-associated factors (TAFIIs): multiple, selective
transcriptional mediators in common complexes. Trends
Biochem Sci. 2000 Feb;25(2):59-63
Panagopoulos I, Mencinger M, Dietrich CU, Bjerkehagen B,
Saeter G, Mertens F, Mandahl N, Heim S. Fusion of the
RBP56 and CHN genes in extraskeletal myxoid
chondrosarcomas
with
translocation
t(9;17)(q22;q11).
Oncogene. 1999 Dec 9;18(52):7594-8
This article should be referenced as such:
Huret JL. TAF15 (TAF15 TAF15 RNA polymerase II, TATA box
binding protein (TBP)-associated factor, 68kDa). Atlas Genet
Cytogenet Oncol Haematol. 2000; 4(4):190-191.
Sjögren H, Meis-Kindblom J, Kindblom LG, Aman P, Stenman
G. Fusion of the EWS-related gene TAF2N to TEC in
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Huret JL
191
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
PRDX1 (peroxiredoxin 1)
Maité P Prosperi, Didier Ferbus, Gérard Goubin
Laboratoire d'Oncogenese, UMR147 CNRS, Section de recherche, Institut Curie, Paris, France (MPP, DF,
GG)
Published in Atlas Database: October 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/PAGID266.html
DOI: 10.4267/2042/37668
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
References
Other names: PRX1
Location: 1p34.1 (pseudogene 9p22)
Prospéri MT, Ferbus D, Karczinski I, Goubin G. A human
cDNA corresponding to a gene overexpressed during cell
proliferation encodes a product sharing homology with
amoebic and bacterial proteins. J Biol Chem. 1993 May
25;268(15):11050-6
DNA/RNA
Prospéri MT, Apiou F, Dutrillaux B, Goubin G. Organization
and chromosomal assignment of two human PAG gene loci:
PAGA encoding a functional gene and PAGB a processed
pseudogene. Genomics. 1994 Jan 15;19(2):236-41
Description
6 exons, 13 kb.
Protein
This article should be referenced as such:
Prosperi MP, Ferbus D, Goubin G. PRDX1 (peroxiredoxin
1). Atlas Genet Cytogenet Oncol Haematol. 2000;
4(4):192.
Expression
In proliferating tissues.
Localisation
Cytosolic.
Function
Unknown, overexpressed following induction of
proliferation and oxidative stress.
Homology
Thioperoxyredoxines.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
192
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
PML (Promyelocytic leukemia)
Franck Viguié
Laboratoire de Cytogénétique - Service d'Hématologie Biologique, Hôpital Hôtel-Dieu, 75181 Paris Cedex
04, France (FV)
Published in Atlas Database: October 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/PMLID41.html
DOI: 10.4267/2042/37669
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
rich C-terminal region, of unknown function, variable
in length (alternative splicing) and containing
phosphorylation sites.
Identity
Other names: MYL (myelocytic leukemia)
HGNC (Hugo): PML
Location: 15q24
Expression
In a wide variety of tissues. In hematopoietic tissue,
expression apparently restricted to myeloid precursors.
Localisation
Nuclear, as part of a multiproteic complex located into
multiple subnuclear PML oncogenic domains (PODs).
Function
Unknown to date; putative transcription factor; in
conjunction with other proteins included in the PODs,
it would play a role as tumor suppressor and in
apoptosis.
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular
Cytogenetics.
DNA/RNA
Homology
Description
With (numerous) other RING finger/B box proteins.
9 coding exons; total gene sequence: 35 kb ?
Implicated in
Transcription
t(15;17)(q22;q21) / acute promyelocytic
leukemia (APL) --> PML-RARA
3 main mRNAs 4.6, 3.0 and 2.1 kb; alternative splicing
generates at least 16 isoforms of mRNAs, varying in
the region coding for the C-terminal part of the protein.
Disease
Typical APL (or M3 ANLL, FAB classification),
approximately 98% of APL cases; abnormal
promyelocytes with Auer rods and bundles (faggots);
disruption of the PODs with a microspeckeled pattern;
maturation response to all-trans retinoic acid (ATRA)
therapy.
Prognosis
Immediate prognosis impaired by intravascular
disseminated coagulopathy; long term prognosis is
favorable with treatment combining ATRA plus
chemotherapy.
Protein
Description
560 amino acids, 70 KDa (longest isoform); composed
successively, from the N- to the C-terminus, by: 1- a
proline-rich N-terminus 2- a so-called "tripartite motif",
cysteine-histidine rich, composed of a RING finger
structure and 2 B box domains, with putative DNAbinding function 3- a coiled-coil motif corresponding to
a dimerization interface 4- a basic sequence with a
nuclear localization domain, and 5- a serine-proline
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
193
PML (Promyelocytic leukemia)
Viguié F
Kakizuka A, Miller WH Jr, Umesono K, Warrell RP Jr, Frankel
SR, Murty VV, Dmitrovsky E, Evans RM. Chromosomal
translocation t(15;17) in human acute promyelocytic leukemia
fuses RAR alpha with a novel putative transcription factor,
PML. Cell. 1991 Aug 23;66(4):663-74
Cytogenetics
Variant or complex t(15;17) translocation in 5% of
cases, no known prognosis implication; secondary
chromosomal abnormalities in 30 to 35% of APL at
diagnosis; association with +8 in 17 to 28% of cases;
other associations are rare but recurrent: del(7q),
del(9q), ider(17)t(15;17), +21.
Hybrid/Mutated gene
The crucial fusion transcript is 5'PML-3'RARA,
encoded by der(15) chromosome; the counterpart
5'RARA-3'PML encoded by der(17) is inconstant.
Breakpoint in RARA gene is always located in intron
between A and B domains.
Three breakpoint clusters in PML gene: bcr1 (70% of
patients), bcr2 (10%) and bcr3 (20%), giving rise
respectively to the long (L), intermediate (V) and short
(S) length hybrid PML-RARAtranscripts; V form
would be linked to ATRA decreased sensitivity and S
form to association with an excess of secondary
chromosome changes.
Abnormal protein
106 Kda fusion protein; role in the leukemogenic
process by probable interference with the signalling
pathway leading to differentiation and maturation of
myeloid precursors (mainly dysregulation of retinoidinducible genes involved in myeloid differentiation).
Nervi C, Poindexter EC, Grignani F, Pandolfi PP, Lo Coco F,
Avvisati G, Pelicci PG, Jetten AM. Characterization of the
PML-RAR alpha chimeric product of the acute promyelocytic
leukemia-specific t(15;17) translocation. Cancer Res. 1992 Jul
1;52(13):3687-92
Chen Z, Tong JH, Dong S, Zhu J, Wang ZY, Chen SJ. Retinoic
acid regulatory pathways, chromosomal translocations, and
acute promyelocytic leukemia. Genes Chromosomes Cancer.
1996 Mar;15(3):147-56
Casini T, Grignani F, Pelicci PG. Genetics of APL and the
molecular basis of retinoic acid treatment. Int J Cancer. 1997
Feb 7;70(4):473-4
Hodges M, Tissot C, Howe K, Grimwade D, Freemont PS.
Structure, organization, and dynamics of promyelocytic
leukemia protein nuclear bodies. Am J Hum Genet. 1998
Aug;63(2):297-304
Grimwade D. The pathogenesis of acute promyelocytic
leukaemia: evaluation of the role of molecular diagnosis and
monitoring in the management of the disease. Br J Haematol.
1999 Sep;106(3):591-613
Melnick A, Licht JD. Deconstructing a disease: RARalpha, its
fusion partners, and their roles in the pathogenesis of acute
promyelocytic leukemia. Blood. 1999 May 15;93(10):3167-215
Zhong S, Salomoni P, Pandolfi PP. The transcriptional role of
PML and the nuclear body. Nat Cell Biol. 2000 May;2(5):E8590
References
This article should be referenced as such:
de Thé H, Chomienne C, Lanotte M, Degos L, Dejean A. The
t(15;17) translocation of acute promyelocytic leukaemia fuses
the retinoic acid receptor alpha gene to a novel transcribed
locus. Nature. 1990 Oct 11;347(6293):558-61
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Viguié F. PML (Promyelocytic leukemia). Atlas
Cytogenet Oncol Haematol. 2000; 4(4):193-194.
194
Genet
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
RARA (Retinoic acid receptor, alpha)
Franck Viguié
Laboratoire de Cytogénétique - Service d'Hématologie Biologique, Hôpital Hôtel-Dieu, 75181 Paris Cedex
04, France (FV)
Published in Atlas Database: October 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/RARAID46.html
DOI: 10.4267/2042/37670
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Function
Identity
Ligand-dependent transcription factor specifically
involved in hematopoietic cells differentiation and
maturation = receptor for all-trans retinoic acid
(ATRA) and 9-cis RA which are intracellular
metabolites of vitamine A, active in cellular
differentiation and morphogenesis.
After linking with ATRA, RARA binds with a high
affinity as a heterodimer with RXR (retinoid X receptor
protein) to the RARE domain (retinoic acid response
elements), a DNA sequence common to a number of
genes and located in their promoter.
The gene response to RARA binding is modulated by a
series of co-repressors and co-activators.
HGNC (Hugo): RARA
Location: 17q12
c-RARA (17q21) in normal cells: PAC 833D9 - Courtesy
Mariano Rocchi, Resources for Molecular Cytogenetics.
Homology
DNA/RNA
with RARB and RARG (retinoic acid receptors beta
and gamma), 9-cis RA receptors (RXRs) and receptors
for thyroid and steroid hormones and for vitamine D3.
Description
9 exons; total gene sequence: 7450 bp.
Implicated in
Transcription
t(15;17)(q22;q12) / acute promyelocytic
leukemia (APL) -->PML - RARA
2.8 and 3.6 kb transcripts.
Protein
Disease
Typical APL (or M3 ANLL, FAB classification),
approximately 98% of APL cases; abnormal
promyelocytes with Auer rods and bundles (faggots);
disruption of the PODs with a microspeckeled pattern;
maturation response to all-trans retinoic acid (ATRA)
therapy.
Prognosis
Immediate prognosis impaired by intravascular
disseminated coagulopathy; long term prognosis is
favorable with treatment combining ATRA plus
chemotherapy.
Description
462 amino acids - 5 functional domains A/B
(transcriptional regulation), C (DNA binding domain,
contains 2 zinc fingers), D (cellular localization signal),
E (ligand-binding domain) and F (function?).
Expression
In hematopoietic cells.
Localisation
Nuclear.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
195
RARA (Retinoic acid receptor, alpha)
Viguié F
Cytogenetics
Variant or complex t(15;17) translocation in 5% of
cases, no known prognosis implication; secondary
chromosomal abnormalities in 30 to 35% of APL at
diagnosis; association with +8 in 17 to 28% of cases;
other associations are rare but recurrent: del(7q),
del(9q), ider(17)t(15;17), +21.
Hybrid/Mutated gene
The crucial fusion transcript is 5'PML-3'RARA,
encoded by der(15) chromosome; the counterpart
5'RARA-3'PML encoded by der(17) is inconstant.
Breakpoint in RARA gene is always located in intron
between A and B domains.
Three breakpoint clusters in PML gene: bcr1 (70% of
patients), bcr2 (10%) and bcr3 (20%), giving rise
respectively to the long (L), intermediate (V) and short
(S) length hybrid PML-RARAtranscripts; V form
would be linked to ATRA decreased sensitivity and S
form to association with an excess of secondary
chromosome changes.
Abnormal protein
106 Kda fusion protein; role in the leukemogenic
process by probable interference with the signalling
pathway leading to differentiation and maturation of
myeloid precursors (mainly dysregulation of retinoidinducible genes involved in myeloid differentiation).
t(11;17)(q13;q12) / acute promyelocytic
leukemia --> NuMA-RARA
t(11;17)(q23;q12) / acute promyelocytic
leukemia -->PLZF-RARA
Casini T, Grignani F, Pelicci PG. Genetics of APL and the
molecular basis of retinoic acid treatment. Int J Cancer. 1997
Feb 7;70(4):473-4
Disease
Variant acute promyelocytic leukemia (APL) form with
atypical cytologic aspects (intermediate morphology
between M2 and M3, no Auer rods) and no response to
ATRA therapy; less than 1% of APL cases.
Grimwade D. The pathogenesis of acute promyelocytic
leukaemia: evaluation of the role of molecular diagnosis and
monitoring in the management of the disease. Br J Haematol.
1999 Sep;106(3):591-613
Disease
Exceptional: probable response to ATRA.
t(11;17)(q23;q12) / M5 acute non
lymphocytic leukemia --> MLL-RARA
Disease
1 case to date; not to be confused with the
t(11;17)(q23;q12) mentioned above; not found in APL;
belongs to the MLL/11q23 leukemias.
References
de Thé H, Chomienne C, Lanotte M, Degos L, Dejean A. The
t(15;17) translocation of acute promyelocytic leukaemia fuses
the retinoic acid receptor alpha gene to a novel transcribed
locus. Nature. 1990 Oct 11;347(6293):558-61
Kakizuka A, Miller WH Jr, Umesono K, Warrell RP Jr, Frankel
SR, Murty VV, Dmitrovsky E, Evans RM. Chromosomal
translocation t(15;17) in human acute promyelocytic leukemia
fuses RAR alpha with a novel putative transcription factor,
PML. Cell. 1991 Aug 23;66(4):663-74
Nervi C, Poindexter EC, Grignani F, Pandolfi PP, Lo Coco F,
Avvisati G, Pelicci PG, Jetten AM. Characterization of the
PML-RAR alpha chimeric product of the acute promyelocytic
leukemia-specific t(15;17) translocation. Cancer Res. 1992 Jul
1;52(13):3687-92
Melnick A, Licht JD. Deconstructing a disease: RARalpha, its
fusion partners, and their roles in the pathogenesis of acute
promyelocytic leukemia. Blood. 1999 May 15;93(10):3167-215
t(5;17)(q35;q12) / acute promyelocytic
leukemia --> NPM-RARA
This article should be referenced as such:
Disease
Exceptional; probable response to ATRA.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Viguié F. RARA (Retinoic acid receptor, alpha). Atlas Genet
Cytogenet Oncol Haematol. 2000; 4(4):195-196.
196
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
ZNF146 (zinc finger protein 146)
Gérard Goubin
Laboratoire d'Oncogenèse, UMR147 CNRS, Section de recherche, Institut Curie, Paris, France (GG)
Published in Atlas Database: October 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/OZFID267.html
DOI: 10.4267/2042/37667
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
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Identity
Implicated in
Other names: OZF
HGNC (Hugo): ZNF146
Location: 19q13.1
Protein
Disease
Tumors of the exocrine pancreas.
Cytogenetics
Amplification of the 19q13.1 region in a subset of
pancreatic tumors.
Description
References
33 kDa; a kruppel zinc finger protein consisting of 10
zinc finger motives, preceeded by 10 amino acids and
followed by 2 amino acids.
Le Chalony C, Prospéri MT, Haluza R, Apiou F, Dutrillaux B,
Goubin G. The OZF gene encodes a protein consisting
essentially of zinc finger motifs. J Mol Biol. 1994 Feb
18;236(2):399-404
Expression
In most proliferating tissues.
This article should be referenced as such:
Localisation
Goubin G. ZNF146 (zinc finger protein 146). Atlas Genet
Cytogenet Oncol Haematol. 2000; 4(4):197.
Nucleus.
Function
Represse gene expression through a consensus motive.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
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Leukaemia Section
Short Communication
Fibrogenesis imperfecta ossium
Daniel Bontoux, Michel Alcalay, Jean-Loup Huret
Service de Rhumatologie, Centre Hospitalier Universitaire, 86021 Poitiers, France (DB, MA); Genetics,
Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)
Published in Atlas Database: September 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/FibrogImperfOsID1190.html
DOI: 10.4267/2042/37671
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
X-rays of the cervical, thoracic, and lumbar spine (from left to right), and of the pelvic girdle (bottom) showing a marked demineralization
with paucity of coarse, essentially vertical, trabeculae.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
198
Fibrogenesis imperfecta ossium
Bontoux D et al.
Baker SL, Dent CE, Friedman M, Watson L. Fibrogenesis
imperfecta ossium. J Bone Joint Surg Br. 1966 Nov;48(4):80425
Disease
Disorder of bone mineralization with abnormal bone
collagen morphology often associated with monoclonal
gammopathy; may well be a clinical variant of multiple
myeloma.
Thomas WC Jr, Moore TH. Fibrinogenesis imperfecta ossium.
Trans Am Clin Climatol Assoc. 1969;80:54-62
Frame B, Frost HM, Pak CY, Reynolds W, Argen RJ.
Fibrogenesis imperfecta ossium. A collagen defect causing
osteomalacia. N Engl J Med. 1971 Sep 30;285(14):769-72
Etiology
Presents as an acquired metabolic bone disease of
unknown aetiology; may also be a genetic disorder (at
least in some cases), since a father and his daugther
were affected.
Golde D, Greipp P, Sanzenbacher L, Gralnick HR.
Hematologic abnormalities in fibrogenesis imperfecta ossium. J
Bone Joint Surg Am. 1971 Mar;53(2):365-70
Camus JP, Perie G, Brocheriou C, Crouzet J, Prier A, Cros F.
[Fibrogenesis imperfecta ossium. Study of 2 cases in the same
family]. Ann Med Interne (Paris). 1975 Aug-Sep;126(8-9):583-9
Epidemiology
25 cases diagnosed to date; onset of symptoms mostly
in 50-60 yr-old patients.
Swan CH, Shah K, Brewer DB, Cooke WT. Fibrogenesis
imperfecta ossium. Q J Med. 1976 Apr;45(178):233-53
Clinics
A combination of progressive and incapacitating bone
pain and spontaneous, multiple fractures typically
localized at tendon insertion sites; leads to extreme
bone fragility, progressive immobility and usually
results in the patient becoming bedridden.
Serum alkaline phosphatase can be raised; monoclonal
gammopathy is found in 25% of cases; 10 to 20%
atypical plasma cells can be found in the bone marrow;
however, evolution towards myeloma has never been
reported.
No other organ involvement has yet been reported.
Diagnosis on bone biopsy showing the collagen defect.
Christmann D, Wenger JJ, Dosch JC, Schraub M,
Wackenheim A. [Axial osteomalacia. Comparative analysis
with fibrogenesis imperfecta ossium (author's transl)]. J Radiol.
1981 Jan;62(1):37-41
Pathology
Byers PD, Stamp TC, Stoker DJ. Case report 296.
Fibrogenesis imperfecta. Skeletal Radiol. 1985;13(1):72-6
Pinto F, Bonucci E, Mezzelani P, Cetta G, De Sandre G.
Fibrogenesis imperfecta ossium (clinical, biochemical and
ultrastructural investigations). Ital J Orthop Traumatol. 1981
Dec;7(3):371-85
Byron M, Woods CG. Fibrogenesis imperfecta ossium. Metab
Bone Dis Rel Res. 1984;5:210-5.
Stoddart PG, Wickremaratchi T, Hollingworth P, Watt I.
Fibrogenesis imperfecta ossium. Br J Radiol. 1984
Aug;57(680):744-51
Mimics
osteomalacia
with
abnormal
bone
mineralization but there is complete loss of the
birefringence characteristic of oriented collagen fibers;
at ultrastructural level the normal lamellar pattern of
collagen fibers is replaced by curved and extremely
variable in thickness collagen fibrils.
Stamp TC, Byers PD, Ali SY, Jenkins MV, Willoughby JM.
Fibrogenesis imperfecta ossium: remission with melphalan.
Lancet. 1985 Mar 9;1(8428):582-3
Lang R, Vignery AM, Jensen PS. Fibrogenesis imperfecta
ossium with early onset: observations after 20 years of illness.
Bone. 1986;7(4):237-46
Treatment
Pombo FF, Arrojo Suarez de Centi L Verela Romero JR,
Martin Egana R, Amal Monreal F. Fibrogenesis imperfecta
ossium. Radiologia. 1987;29:469-72.
Treatment with melphalan and corticosteroids over
years has been successful in a number (but not all) of
cases.
Ralphs JR, Stamp TC, Dopping-Hepenstal PJ, Ali SY.
Ultrastructural features of the osteoid of patients with
fibrogenesis imperfecta ossium. Bone. 1989;10(4):243-9
Prognosis
Median survival is about 3 yrs.
Carr AJ, Smith R, Athanasou N, Woods CG. Fibrogenesis
imperfecta ossium. J Bone Joint Surg Br. 1995 Sep;77(5):8209
Genetics
Lafage-Proust M, Schaeverbeke T, Dehais J. Fibrogenesis
imperfecta ossium: ineffectiveness of melphalan. Calcif Tissue
Int. 1996 Oct;59(4):240-4
Note
Genes involved in the cases possibly inherited, if any,
are unknown; genes involved in the plasma cells
proliferation are also unknown.
Wang CS, Steinbach LS, Campbell JB, Hayashi G, Yoon ST,
Johnston JO. Fibrogenesis imperfecta ossium: imaging
correlation in three new patients. Skeletal Radiol. 1999
Jul;28(7):390-5
References
Baker SL, Turnbull HM. Two cases of a hitherto undescribed
disease characterized by a gross defect in the collagen of the
bone matrix. J Pathol Bacteriol. 1950;62:132-4.
This article should be referenced as such:
Bontoux D, Alcalay M, Huret JL. Fibrogenesis imperfecta
ossium. Atlas Genet Cytogenet Oncol Haematol. 2000;
4(4):198-199.
BAKER SL. Fibrogenesis imperfecta ossium; a generalised
disease of bone characterised by defective formation of the
collagen fibres of the bone matrix. J Bone Joint Surg Br. 1956
Feb;38-B(1):378-417
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
199
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Leukaemia Section
Mini Review
Chronic myelogenous leukaemia (CML)
Ali G Turhan
Translational Research - Cell Therapy, Laboratory, Institut Gustave Roussy, INSERM U. 362, 1 - 39, rue
Camille Desmoulins, 94805 Villejuif Cedex, France (AGT)
Published in Atlas Database: October 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/CML.html
DOI: 10.4267/2042/37672
This article is an update of: Huret JL. Chronic myelogenous leukaemia (CML). Atlas Genet Cytogenet Oncol Haematol.1997;1(2):89-91.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Prognosis
Clinics and pathology
Median survival: 4 years with conventional therapy
(hydroxyurea, busulfan), 6 years with aIFN therapy;
allogeneic bone marrow transplantation may cure the
patient; otherwise, the best treatment to date associates
interferon a, hydroxyurea and cytarabine.
Disease
CML is a malignant chronic myeloproliferative
disorder (MPD) of the hematopoietic stem cell.
Phenotype/cell stem origin
Cytogenetics
Evidence exists for the involvement of the most
primitive and quiescent hematopoietic stem cell
compartiment (CD34+/CD38-, Thy1+): t(9;22) is found
in myeloid progenitor and in B-lymphocytes
progenitors, but, involvement of the T-cell lineage is
extremely rare.
Cytogenetics morphological
All CML have a t(9;22), at least at the molecular level
(see below); but not all t(9;22) are found in CML: this
translocation may also be seen in ALL, and in ANLL
(see: t(9;22)(q34;q11) in ALL, t(9;22)(q34;q11) in
ANLL), and the same genes are involved in the three
diseases; in CML, the chromosomal anomaly persists
during remission, in contrast with AL cases.
Epidemiology
Annual incidence: 10/106 (from 1/106 in childhood to
30/106 after 60 years); median age: 30-60 years; sex
ratio: 1.2M/1F.
Cytogenetics molecular
Clinics
Is a useful tool for diagnostic ascertainment in the case
of a 'masked Philadelphia' chromosome, where
chromosomes 9 and 22 all appear to be normal, but
where cryptic insertion of 3' ABL within a
chromosome 22 can be demonstrated.
Splenomegaly; chronic phase (lasts about 3 years) with
maintained cell's normal activities, followed by
accelerated phase(s) (blasts still 30%; blood data:
WBC:100 X 109/l and more during chronic phase, with
basophilia; a few blasts; thrombocytosis may be
present; low leucocyte alkaline phosphatases; typical
acute leukaemia (AL) blood data at the time of myeloid
or lymphoid-type blast crisis.
Additional anomalies
1- May be present at diagnosis (in 10%, possibly with
unfavourable significance), or may appear during
course of the disease, they do not indicate the
imminence of a blast crisis, although these additional
anomalies also emerge frequently at the time of acute
transformation;
2- These are: +der(22), +8, i(17q), +19, most often, but
also: +21, -Y, -7, -17, +17; acute transformation can
also be accompanied with t(3;21)(q26;q22) (1% of
cases); near haploidy can occur; of note, although rare,
Cytology
Hyperplastic bone marrow; granulocytes proliferation,
with maturation; followed by typical AL cytology (see:
t(9;22)(q34;q11) in ALL, t(9;22)(q34;q11) in ANLL).
Treatment
alphaIFN therapy or allogeneic bone marrow
transplantation (BMT), donor leukocytes infusions.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
200
Chronic myelogenous leukaemia (CML)
Turhan AG
is the occurrence of chromosome anomalies which are
typical of a given BC phenotype (e.g. t(15;17) in a
promyelocytic transformation, dic(9;12) in a CD10+
lymphoblastic BC...); +8, +19, +21, and i(17q) occur
more often in myeloid -rather than lymphoid- blast
crises and apparent t(V;22) or t(9;V), where V is a
variable.
b1 to b5 of M-bcr; most breakpoints being either
between b2 and b3, or between b3 and b4.
Transcript
8.5 kb mRNA, resulting in a 210 kDa chimeric protein.
Detection
RT-PCR for minimal residual disease detection.
Variants
Fusion protein
Chromosome, are found in 5-10% of cases; however,
9q34-3'ABL always joins 22q11-5'BCR in true CML;
the third chromosome and breakpoint is, at times, not
random. In a way, masked Philadelphia chromosomes
(see above) are also variants.
Description
P210 with the first 902 or 927 amino acids from BCR;
BCR/ABL has a cytoplasmic localization, in contrast
with ABL, mostly nuclear. It is now clearly established
that BCR-ABL is the oncogene responsible for the
occurrence of CML. The hybrid protein has an
increased protein kinase activity compared to ABL:
3BP1 (binding protein) binds normal ABL on SH3
domain, which prevents SH1 activation; with
BCR/ABL, the first (N-terminal) exon of BCR binds to
SH2, hidding SH3 which, as a consequence, cannot be
bound to 3BP1; thereof, SH1 is activated.
Oncogenesis
A- Major molecular pathways activated by BCR-ABL.
1- BCR/ABL activates RAS signaling through the
GRB2 adaptor molecule which interacts specifically
with the Y177 of BCR.
2- PI3-K (phosphatidyl inositol 3' kinase) pathway is
also activated with secondary activation of the
AKT/PKB pathway.
3- Integrity of transcription machinery induced by
MYC is necessary for the transforming action of BCRABL.
4- More recently, activation of STAT (Signal
transducers and activators of transcription) molecules
has been described as a major molecular signaling
event induced by BCR-ABL, with activation of
essentially STAT5, 1, and 6.
5- Activation of the molecules of the focal adhesion
complex (PAXILLIN, FAK) by BCR-ABL requires the
role of the adaptor molecule CRK-L.
6- BCR-ABL activates negative regulatory molecules
such as PTP1B and Abi-1 and their inactivation could
be associated with progression into blast crisis.
B- Correlations between molecular pathways and
leukemic phenotype observed in primary CML cells or
in BCR-ABL-transduced cells are currently limited.
1BCR-ABL
has
anti-apoptotic
activity
(PI63K/Akt/STAT5).
2- BCR/ABL induces cell adhesive and migratory
abnormalities in vitro in the presence of fibronection or
in
transwell
assays
(Abnormal
integrin
signaling/FAK/CRK-L/Abnormal
response
to
chemokine SDF-1).
3- BCR-ABL induces a dose-effect relationship in
CML cells with increased BCR-ABL mRNA during
progression into blast crisis, with induction of genetic
instability.
Genes involved and proteins
ABL
Location
9q34
DNA/RNA
Alternate splicing (1a and 1b) in 5'.
Protein
Giving rise to 2 proteins of 145 kDa; contains SH (SRC
homology) domains; N-term SH3 and SH2 - SH1
(tyrosine kinase) - DNA binding motif - actin binding
domain C-term; widely expressed; localisation is
mainly nuclear; inhibits cell growth.
BCR
Location
22q11
DNA/RNA
Various splicings.
Protein
Main form: 160 kDa; N-term Serine-Treonine kinase
domain, SH2 binding, and C-term domain which
functions as a GTPase activating protein for p21rac;
widely expressed; cytoplasmic localisation; protein
kinase; probable role in signal transduction.
Result of the chromosomal
anomaly
Hybrid gene
Description
1- The crucial event lies on der(22), id est 5' BCR/3'
ABL hybrid gene is pathogenic, while ABL/BCR may
or may not be expressed;
2- Breakpoint in ABL is variable over a region of 200
kb, often between the two alternative exons 1b and 1a,
sometimes 5' of 1b, or 3' of 1a, but always 5' of exon 2;
3- Breakpoint in BCR is in a narrow region, therefore
called M-bcr (for major breakpoint cluster region), a
cluster of 5.8 kb, between exons 12 and 16, also called
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
201
Chronic myelogenous leukaemia (CML)
Turhan AG
Enright H, McGlave PB. Chronic myelogenous leukemia. Curr
Opin Hematol. 1995 Jul;2(4):293-9
4- Molecular events associated with blast crisis: P53
mutation, methylation of ABL promoter, telomere
shortening, Abl-1 inactivation.
Bazzoni G, Carlesso N, Griffin JD, Hemler ME. Bcr/Abl
expression stimulates integrin function in hematopoietic cell
lines. J Clin Invest. 1996 Jul 15;98(2):521-8
To be noted
Ilaria RL Jr, Van Etten RA. P210 and P190(BCR/ABL) induce
the tyrosine phosphorylation and DNA binding activity of
multiple specific STAT family members. J Biol Chem. 1996
Dec 6;271(49):31704-10
Note
1- Blast crisis is sometimes at the first onset of CML,
and those cases may be undistinguishable from true
ALL or ANLL with t(9;22) and P210 BCR/ABL
hybrid;
2- JCML (juvenile chronic myelogenous leukaemia) is
not the juvenile form of chronic myelogenous
leukaemia: there is no t(9;22) nor BCR/ABL hybrid in
JCML, and clinical features (including a worse
prognosis) are not similar to those found in CML;
3- so called BCR/ABL negative CML should not be
called so!
4- P53 is altered in 1/3 of BC-CML cases.
5- Most recent developments: Evidence of telomere
shortening in CML cells during progression into blast
crisis.
Gotoh A, Broxmeyer HE. The function of BCR/ABL and related
proto-oncogenes. Curr Opin Hematol. 1997 Jan;4(1):3-11
Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau JL,
Maloisel F, Bouabdallah R, Guyotat D, Cheron N, Nicolini F,
Abgrall JF, Tanzer J. Interferon alfa-2b combined with
cytarabine versus interferon alone in chronic myelogenous
leukemia. French Chronic Myeloid Leukemia Study Group. N
Engl J Med. 1997 Jul 24;337(4):223-9
Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M,
Martinez R, Choi JK, Trotta R, Wlodarski P, Perrotti D, Chan
TO, Wasik MA, Tsichlis PN, Calabretta B. Transformation of
hematopoietic cells by BCR/ABL requires activation of a PI3k/Akt-dependent
pathway.
EMBO
J.
1997
Oct
15;16(20):6151-61
Ahmed M, Dusanter-Fourt I, Bernard M, Mayeux P, Hawley
RG, Bennardo T, Novault S, Bonnet ML, Gisselbrecht S, Varet
B, Turhan AG. BCR-ABL and constitutively active
erythropoietin receptor (cEpoR) activate distinct mechanisms
for growth factor-independence and inhibition of apoptosis in
Ba/F3 cell line. Oncogene. 1998 Jan 29;16(4):489-96
References
Sokal JE, Gomez GA, Baccarani M, Tura S, Clarkson BD,
Cervantes F, Rozman C, Carbonell F, Anger B, Heimpel H.
Prognostic significance of additional cytogenetic abnormalities
at diagnosis of Philadelphia chromosome-positive chronic
granulocytic leukemia. Blood. 1988 Jul;72(1):294-8
Dai Z, Quackenbush RC, Courtney KD, Grove M, Cortez D,
Reuther GW, Pendergast AM. Oncogenic Abl and Src tyrosine
kinases elicit the ubiquitin-dependent degradation of target
proteins through a Ras-independent pathway. Genes Dev.
1998 May 15;12(10):1415-24
Huret JL. Complex translocations, simple variant translocations
and Ph-negative cases in chronic myelogenous leukaemia.
Hum Genet. 1990 Oct;85(6):565-8
Dai Z, Quackenbush RC, Courtney KD, Grove M, Cortez D,
Reuther GW, Pendergast AM. Oncogenic Abl and Src tyrosine
kinases elicit the ubiquitin-dependent degradation of target
proteins through a Ras-independent pathway. Genes Dev.
1998 May 15;12(10):1415-24
Heisterkamp N, Groffen J. Molecular insights into the
Philadelphia translocation. Hematol Pathol. 1991;5(1):1-10
Kurzrock R, Talpaz M. The molecular pathology of chronic
myelogenous leukaemia. Br J Haematol. 1991 Oct;79 Suppl
1:34-7
LaMontagne KR Jr, Flint AJ, Franza BR Jr, Pandergast AM,
Tonks NK. Protein tyrosine phosphatase 1B antagonizes
signalling by oncoprotein tyrosine kinase p210 bcr-abl in vivo.
Mol Cell Biol. 1998 May;18(5):2965-75
Martiat P, Michaux JL, Rodhain J. Philadelphia-negative (Ph-)
chronic myeloid leukemia (CML): comparison with Ph+ CML
and chronic myelomonocytic leukemia. The Groupe Français
de Cytogénétique Hématologique. Blood. 1991 Jul
1;78(1):205-11
Brümmendorf TH, Holyoake TL, Rufer N, Barnett MJ, Schulzer
M, Eaves CJ, Eaves AC, Lansdorp PM. Prognostic implications
of differences in telomere length between normal and
malignant cells from patients with chronic myeloid leukemia
measured by flow cytometry. Blood. 2000 Mar 15;95(6):188390
Gale RP, Grosveld G, Canaani E, Goldman JM. Chronic
myelogenous leukemia: biology and therapy. Leukemia. 1993
Apr;7(4):653-8
Oda T, Heaney C, Hagopian JR, Okuda K, Griffin JD, Druker
BJ. Crkl is the major tyrosine-phosphorylated protein in
neutrophils from patients with chronic myelogenous leukemia.
J Biol Chem. 1994 Sep 16;269(37):22925-8
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
This article should be referenced as such:
Turhan AG. Chronic myelogenous leukaemia (CML). Atlas
Genet Cytogenet Oncol Haematol. 2000; 4(4):200-202.
202
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
Hairy Cell Leukemia (HCL)
Leukemia Variant (HCL-V)
and
Hairy
Cell
Vasantha Brito-Babapulle, Estella Matutes, Daniel Catovsky
Academic Department of Haematology and Cytogenetics, The Royal Marsden NHS Trust, London, UK
(EM)
Published in Atlas Database: October 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/HairyCellID2036.html
DOI: 10.4267/2042/37673
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
cytoplasmic villi and is intermediate in morphology
between HCL and B-prolymphocytic leukaemia. HCL
cells show strong acid phosphatase reaction which is
resistant to tartaric acid.
Clinics and pathology
Phenotype/cell stem origin
Cells from hairy cell leukemia (HCL) and hairy cell
leukemia variant (HCL-V) have a distinct
immunophenotype which is of a mature but not
terminally differentiated activated B-cell. Although
some similarities exist between these two conditions
like the expression of B-cell activation marker CD103,
CD11c and IgG heavy chain expression, differences
exists between these two diseases. HCL is positive for
CD25 (anti IL2 receptor) and HC2 while HCL-V is
negative for CD25 and HC2.
Pathology
The bone marrow and spleen histology is identical in
HCL and HCL-V. The bone marrow shows a distinct
pattern of interstital infiltration by lymphoid cells with
spaces among them ('fried egg' pattern). Reticulin is
invariably increased in HCL but not in HCL-V. Spleen
histology shows expansion and infiltration of the red
pulp with naked white pulp.
Treatment
Epidemiology
Interferon alpha produces good partial responses in
HCL but invariably the disease relapses. The purine
analogs 2 deoxycorformycin and 2-deoxyadenosine
induce responses in >95% of patients, most of them
complete and durable. HCL-V is not responsive to the
above treatments with only half achieving transient
partial responses to the purine analogs with
splenectomy being the best palliative therapeutic
measure.
First described as leukaemic reticulo endotheliosis,
HCL predominantly affects middle aged males (male
/female ratio = 4) while male predominance is not
observed in HCL-V but they are older.
Clinics
HCL patients present with splenomegaly, cytopenia(s)
and variable proportions of circulating hairy cells.
Monocytopenia is constant, lymphadenopathy is rare
and the bone marrow is "dry tap" in most cases. HCLV patients show most of the above features but have
high white blood cell counts normal numbers of
monocytes and aspirable bone marrow.
Evolution
HCL and HCL-V are characterised by a chronic clinical
course with the symptoms deriving from cytopenias,
and abdominal distension due to splenomegaly. Few
patients undergo transformation.
Cytology
Prognosis
The typical hairy cell is large in size, has an eccentric
and sometimes kidney shaped nucleus and abundant
cytoplasm with long villi which is associated with
alterations in the cytoskeletal architecture. HCL-V has
a central round nucleus, a prominent nucleolus,
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
HCL has a good prognosis .In a large series 80% of
patients survived at 12 years.
HCL -V has a poorer prognosis and in the only largest
series reported the median survival is 9 years.
203
Hairy Cell Leukemia (HCL) and Hairy Cell Leukemia Variant (HCL-V)
Brito-Babapulle V, Pittman S, Melo JV, Parreira L, Catovsky D.
The 14q+ marker in hairy cell leukaemia. A cytogenetic study
of 15 cases. Leuk Res. 1986;10(2):131-8
Cytogenetics
Cytogenetics morphological
Sainati L, Matutes E, Mulligan S, de Oliveira MP, Rani S,
Lampert IA, Catovsky D. A variant form of hairy cell leukemia
resistant to alpha-interferon: clinical and phenotypic
characteristics of 17 patients. Blood. 1990 Jul 1;76(1):157-62
Several reports describe nonclonal or oligoclonal
abnormalities in HCL and in some with clonal
abnormalities translocations involving the 14q32.3 the
site of the IGH locus, rearrangements of 14q22-24 and
abnormalities of chromosomes 11 and 12 have been
described. One study reported a 40% incidence of
chromosome 5 abnormalities.
HCL-V is often characterised by a complex karyotype.
Translocation t(14;18)(q32;q21) observed in follicular
lymphoma and t(2;8)(p12;q24) observed in variant
Burkitt lymphoma have been reported in HCL-V.
May W, Korenberg JR, Chen XN, Lunsford L, Wood WJ,
Thompson A, Wall R, Denny CT. Human lymphocyte-specific
pp52 gene is a member of a highly conserved dispersed
family. Genomics. 1993 Mar;15(3):515-20
Brito-Babapulle V, Matutes E, Oscier D, Mould S, Catovsky D.
Chromosome abnormalities in hairy cell leukaemia variant.
Genes Chromosomes Cancer. 1994 Jul;10(3):197-202
Haglund U, Juliusson G, Stellan B, Gahrton G. Hairy cell
leukemia is characterized by clonal chromosome abnormalities
clustered to specific regions. Blood. 1994 May 1;83(9):2637-45
Cytogenetics molecular
Kayano H, Dyer MJ, Zani VJ, Laffan MA, Matutes E, Asou N,
Katayama I, Catovsky D. Aberrant rearrangements within the
immunoglobulin heavy chain locus in hairy cell leukemia. Leuk
Lymphoma. 1994;14 Suppl 1:41-7
Deletion of the p53 tumour suppressor gene mapping to
chromosome 17p13 occurs with a high incidence in
both HCL and HCL-V. But a significant difference is
observed in the proportion of cells with a deleted allele
in HCL-V compared to HCL (P<0.01) and correlates
with the well known tendency for transformation and
poor response to therapy characteristic of HCL-V.
Matutes E, Morilla R, Owusu-Ankomah K, Houliham A, Meeus
P, Catovsky D. The immunophenotype of hairy cell leukemia
(HCL). Proposal for a scoring system to distinguish HCL from
B-cell disorders with hairy or villous lymphocytes. Leuk
Lymphoma. 1994;14 Suppl 1:57-61
Genes involved and proteins
Bosch F, Campo E, Jares P, Pittaluga S, Muñoz J, Nayach I,
Piris MA, Dewolf-Peeters C, Jaffe ES, Rozman C. Increased
expression of the PRAD-1/CCND1 gene in hairy cell
leukaemia. Br J Haematol. 1995 Dec;91(4):1025-30
Note
Molecular studies suggest that hairy cells have
aberrations in the constant region of the IgM intron
which could be responsible for errors in class switching
and explain the pattern of Ig heavy chain expression in
HCL which does not fit the the class switching model
which occurs in normal B-cell differentiation.
Over expression of the BCL-1 gene on chromosome
11q13 and encoding Cyclin D-1 has been demonstrated
by Northern blot for RNA and Western blot and
immunocytochemistry for protein expression in over
70% of patients with HCL investigated (including
1HCL-V), but with no evidence for chromosomal or
molecular rearrangement of the BCL-1 locus.
The steady state m-RNA and protein levels of the
leucocyte specific gene pp52 coding for a cytoskeletal
protein and binding to filamentous actin (F-actin) is
elevated in HCL.The gene maps to chromosome
11p15.5. Colocalisation of pp52 with F-actin occurs at
the base of the villi. Interferon alpha (IFN alpha) a
highly effective agent in the treatment of HCL has been
shown to reduce pp52 m- RNA and blunt the villi.
de Boer CJ, Kluin-Nelemans JC, Dreef E, Kester MG, Kluin
PM, Schuuring E, van Krieken JH. Involvement of the CCND1
gene in hairy cell leukemia. Ann Oncol. 1996 Mar;7(3):251-6
Fleckenstein E, Dirks W, Dehmel U, Drexler HG. Cloning and
characterization of the human tartrate-resistant acid
phosphatase (TRAP) gene. Leukemia. 1996 Apr;10(4):637-43
Miyoshi E, Wall R, Thompson AA. Aberrant Expression of
leucocyte specific pp52 in hairy cell leukemia (Meeting abstract
). Pros-Annu-Meer A-M Assoc Cancer Research.1996; 37:
A325.
Wong KF, Kwong YL, Hui PK. Hairy cell leukemia variant with
t(2;8)(p12;q24) abnormality. Cancer Genet Cytogenet. 1997
Oct 15;98(2):102-5
Vallianatou K, Brito-Babapulle V, Matutes E, Atkinson S,
Catovsky D. p53 gene deletion and trisomy 12 in hairy cell
leukemia and its variant. Leuk Res. 1999 Nov;23(11):1041-5
Tallman MS and Polliack A Eds. . Hairy cell leukemia.
Advances in Blood Disorders. Harwood academic publishers
2000.
Matutes E, Wotherspoon A, Brito-Babapulle V, Catovsky D.
The natural history and clinico-pathological features of the
variant form of hairy cell leukemia. Leukemia. 2001
Jan;15(1):184-6
References
This article should be referenced as such:
Golomb HM, Catovsky D, Golde DW. Hairy cell leukemia: a
clinical review based on 71 cases. Ann Intern Med. 1978
Nov;89(5 Pt 1):677-83
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Brito-Babapulle V et al.
Brito-Babapulle V, Matutes E, Catovsky D. Hairy Cell
Leukemia (HCL) and Hairy Cell Leukemia Variant (HCL-V).
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):203-204.
204
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
t(9;22)(q34;q11) in CML
Ali G Turhan
Translational Research - Cell Therapy, Laboratory, Institut Gustave Roussy, INSERM U. 362, 1 - 39, rue
Camille Desmoulins, 94805 Villejuif, France (AGT)
Published in Atlas Database: October 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0922CML.html
DOI: 10.4267/2042/37674
This article is an update of: Huret JL. t(9;22)(q34;q11) in CML. Atlas Genet Cytogenet Oncol Haematol.1997;1(2):98-100.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Note
Although the same hybrid genes issued from ABL and BCR are the hallmark of the t(9;22) translocation, this
translocation may be seen in the following diseases: chronic myelogenous leukemia (CML), acute non lymphocytic
leukemia (ANLL), and acute lymphocytic leukemia (ALL), and will therefore be described in the 3 different situations:
t(9;22)(q34;q11) in CML, t(9;22)(q34;q11) in ALL, t(9;22)(q34;q11) in ANLL, t(9;22)(q34;q11) in CML is herein
described.
t(9;22)(q34;q11) G- banding (left) - Courtesy Jean-Luc Lai and Alain Vanderhaegen (3 top) and Diane H. Norback, Eric B. Johnson, and
Sara Morrison-Delap, UW Cytogenetic Services (2 bottom); R-banding (right) top: Editor; 2 others Courtesy Jean-Luc Lai and Alain
Vanderhaegen); diagram and breakpoints (Editor).
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
205
t(9;22)(q34;q11) in CML
Turhan AG
Additional anomalies
Clinics and pathology
1. May be present at diagnosis (in 10%, possibly with
unfavourable significance), or may appear during
course of the disease, they do not indicate the
imminence of a blast crisis, although these additional
anomalies also emerge frequently at the time of acute
transformation;
2. These are: +der(22), +8, i(17q), +19, most often, but
also: +21, -Y, -7, -17, +17; acute transformation can
also be accompanied with t(3;21) (q26;q22) (1% of
cases); near haploidy can occur; of note, although rare,
is the occurrence of chromosome anomalies which are
typical of a given BC phenotype (e.g. t(15;17) in a
promyelocytic transformation, dic(9;12) in a CD10+
lymphoblastic BC ...); +8, +19, +21, and i(17q) occur
more often in myeloid -rather than lymphoid- blast
crises.
Disease
CML: all CML have a t(9;22), at least at the molecular
level (see below); but not all t(9;22) are found in CML,
as already noted.
Phenotype/cell stem origin
Evidence exists for the involvement of the most
primitive and quiescent hematopoietic stem cell
compartiment (CD34+/CD38-, Thy1+): t(9;22) is found
in myeloid progenitor and in B-lymphocytes
progenitors, but, involvement of the T-cell lineage is
extremely rare.
Epidemiology
Annual incidence: 10/106 (from 1/106 in childhood to
30/106 after 60 yrs); median age: 30-60 yrs; sex ratio:
1.2M/1F.
Variants
t(9;22;V) and apparent t(V;22) or t(9;V), where V is a
variable chromosome, are found in 5-10% of cases;
however, 9q34-3'ABL always joins 22q11-5'BCR in
true CML; the third chromosome and breakpoint is, at
times, not random. In a way, masked Philadelphia
chromosomes (see above) are also variants.
Clinics
Splenomegaly; chronic phase (lasts about 3 yrs) with
maintained cell's normal activities, followed by
accelerated phase(s) (blasts still < 15%), and blast crisis
(BC-CML) with blast cells > 30%; blood data: WBC:
100 X 109/l and more during chronic phase, with
basophilia; a few blasts; thrombocytosis may be
present; low leucocyte alkaline phosphatases; typical
acute leukaemia (AL) blood data at the time of myeloid
or lymphoid -type blast crisis.
Cytology
Hyperplastic bone marrow; granulocytes proliferation,
with maturation; followed by typical AL cytology (see
t(9;22)(q34;q11)/ANLL, and t(9;22)(q34;q11)/ALL).
Treatment
aIFN therapy or allogeneic bone marrow
transplantation (BMT), donor leukocytes infusions.
Prognosis
Median survival: 4 yrs with conventional therapy
(hydroxyurea, busulfan), 6 yrs with aIFN therapy;
allogeneic bone marrow transplantation may cure the
patient; otherwise, the best treatment to date associates
interferon a, hydroxyurea and cytarabine.
835J22 + 1132H12 and 72M14 Cohybridization of (835J22 +
1132H12; ABL) and 72M14 (BCR) on a CML patient carrying the
t(9;22) translocation. Note the splitting of (835J22 + 1132H12)
(red signal) and the colocalization on Ph chromosome (Ph) Courtesy Mariano Rocchi, Resources for Molecular
Cytogenetics.
Cytogenetics
Genes involved and proteins
Cytogenetics morphological
ABL
The chromosomal anomaly persists during remission,
in contrast with acute leukemia (AL) cases.
Location
9q34
DNA/RNA
Alternate splicing (1a and 1b) in 5'.
Protein
Giving rise to 2 proteins of 145 kDa; contains SH (SRC
homology) domains; N-term SH3 and SH2 - SH1
Cytogenetics molecular
Is a useful tool for diagnostic ascertainment in the case
of a 'masked Philadelphia' chromosome, where
chromosomes 9 and 22 all appear to be normal, but
where cryptic insertion of 3' ABL within a
chromosome 22 can be demonstrated.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
206
t(9;22)(q34;q11) in CML
Turhan AG
(tyrosine kinase) - DNA binding motif - actin binding
domain C-term; widely expressed; localisation is
mainly nuclear; inhibits cell growth.
1. BCR/ABL activates RAS signaling through the
GRB2 adaptor molecule which interacts specifically
with the Y177 of BCR.
2. PI3-K (phosphatidyl inositol 3' kinase) pathway is
also activated with secondary activation of the
AKT/PKB pathway.
3. Integrity of transcription machinery induced by
MYC is necessary for the transforming action of BCRABL.
4. More recently, activation of STAT (Signal
transducers and activators of transcription) molecules
has been described as a major molecular signaling
event induced by BCR-ABL, with activation of
essentially STAT5, 1, and 6.
5. Activation of the molecules of the focal adhesion
complex (PAXILLIN, FAK) by BCR-ABL requires the
role of the adaptor molecule CRK-L.
6. BCR-ABL activates negative regulatory molecules
such as PTP1B and Abi-1 and their inactivation could
be associated with progression into blast crisis.
B- Correlations between molecular pathways and
leukemic phenotype observed in primary CML cells or
in BCR-ABL-transduced cells are currently limited.
1.
BCR-ABL
has
anti-apoptotic
activity
(PI63K/Akt/STAT5).
2. BCR/ABL induces cell adhesive and migratory
abnormalities in vitro in the presence of fibronection or
in
transwell
assays
(Abnormal
integrin
signaling/FAK/CRK-L/Abnormal
response
to
chemokine SDF-1).
3. BCR-ABL induces a dose-effect relationship in
CML cells with increased BCR-ABL mRNA during
progression into blast crisis, with induction of genetic
instability.
4. Molecular events associated with blast crisis: P53
mutation, methylation of ABL promoter, telomere
shortening, Abi-1 inactivation.
BCR
Location
22q11
DNA/RNA
Various splicing.
Protein
Main form: 160 KDa; N-term Serine-Treonine kinase
domain, SH2 binding, and C-term domain which
functions as a GTPase activating protein for p21rac;
widely expressed; cytoplasmic localisation; protein
kinase; probable role in signal transduction.
Result of the chromosomal
anomaly
Hybrid gene
Description
1. The crucial event lies on der(22), id est 5' BCR/3'
ABL hybrid gene is pathogenic, while ABL/BCR may
or may not be expressed;
2. Breakpoint in ABL is variable over a region of 200
kb, often between the two alternative exons 1b and 1a,
sometimes 5' of 1b, or 3' of 1a, but always 5' of exon 2;
3. Breakpoint in BCR is in a narrow region, therefore
called M-bcr (for major breakpoint cluster region), a
cluster of 5.8 kb, between exons 12 and 16, also called
b1 to b5 of M-bcr; most breakpoints being either
between b2 and b3, or between b3 and b4.
Transcript
8.5 kb mRNA, resulting in a 210 KDa chimeric protein.
Detection
RT-PCR for minimal residual disease detection.
To be noted
Fusion protein
Note
1. Blast crisis is sometimes at the first onset of CML,
and those cases may be undistinguishable from true
ALL or ANLL with t(9;22) and P210 BCR/ABL
hybrid;
2. JCML (juvenile chronic myelogenous leukaemia) is
not the juvenile form of chronic myelogenous
leukaemia: there is no t(9;22) nor BCR/ABL hybrid in
JCML, and clinical features (including a worse
prognosis) are not similar to those found in CML;
3. so called BCR/ABL negative CML should not be
called so!
4. P53 is altered in 1/3 of BC-CML cases
5. Most recent developments: Evidence of telomere
shortening in CML cells during progression into blast
crisis.
Description
P210 with the first 902 or 927 amino acids from BCR;
BCR/ABL has a cytoplasmic localization, in contrast
with ABL, mostly nuclear. It is now clearly established
that BCR-ABL is the oncogene responsible for the
occurrence of CML. The hybrid protein has an
increased protein kinase activity compared to ABL:
3BP1 (binding protein) binds normal ABL on SH3
domain, which prevents SH1 activation; with
BCR/ABL, the first (N-terminal) exon of BCR binds to
SH2, hidding SH3 which, as a consequence, cannot be
bound to 3BP1; thereof, SH1 is activated.
Oncogenesis
A- Major molecular pathways activated by BCR-ABL.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
207
t(9;22)(q34;q11) in CML
Turhan AG
References
Gotoh A, Broxmeyer HE. The function of BCR/ABL and related
proto-oncogenes. Curr Opin Hematol. 1997 Jan;4(1):3-11
Sokal JE, Gomez GA, Baccarani M, Tura S, Clarkson BD,
Cervantes F, Rozman C, Carbonell F, Anger B, Heimpel H.
Prognostic significance of additional cytogenetic abnormalities
at diagnosis of Philadelphia chromosome-positive chronic
granulocytic leukemia. Blood. 1988 Jul;72(1):294-8
Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau JL,
Maloisel F, Bouabdallah R, Guyotat D, Cheron N, Nicolini F,
Abgrall JF, Tanzer J. Interferon alfa-2b combined with
cytarabine versus interferon alone in chronic myelogenous
leukemia. French Chronic Myeloid Leukemia Study Group. N
Engl J Med. 1997 Jul 24;337(4):223-9
Huret JL. Complex translocations, simple variant translocations
and Ph-negative cases in chronic myelogenous leukaemia.
Hum Genet. 1990 Oct;85(6):565-8
Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M,
Martinez R, Choi JK, Trotta R, Wlodarski P, Perrotti D, Chan
TO, Wasik MA, Tsichlis PN, Calabretta B. Transformation of
hematopoietic cells by BCR/ABL requires activation of a PI3k/Akt-dependent
pathway.
EMBO
J.
1997
Oct
15;16(20):6151-61
Heisterkamp N, Groffen J. Molecular insights into the
Philadelphia translocation. Hematol Pathol. 1991;5(1):1-10
Kurzrock R, Talpaz M. The molecular pathology of chronic
myelogenous leukaemia. Br J Haematol. 1991 Oct;79 Suppl
1:34-7
Ahmed M, Dusanter-Fourt I, Bernard M, Mayeux P, Hawley
RG, Bennardo T, Novault S, Bonnet ML, Gisselbrecht S, Varet
B, Turhan AG. BCR-ABL and constitutively active
erythropoietin receptor (cEpoR) activate distinct mechanisms
for growth factor-independence and inhibition of apoptosis in
Ba/F3 cell line. Oncogene. 1998 Jan 29;16(4):489-96
Martiat P, Michaux JL, Rodhain J. Philadelphia-negative (Ph-)
chronic myeloid leukemia (CML): comparison with Ph+ CML
and chronic myelomonocytic leukemia. The Groupe Français
de Cytogénétique Hématologique. Blood. 1991 Jul
1;78(1):205-11
Dai Z, Quackenbush RC, Courtney KD, Grove M, Cortez D,
Reuther GW, Pendergast AM. Oncogenic Abl and Src tyrosine
kinases elicit the ubiquitin-dependent degradation of target
proteins through a Ras-independent pathway. Genes Dev.
1998 May 15;12(10):1415-24
Gale RP, Grosveld G, Canaani E, Goldman JM. Chronic
myelogenous leukemia: biology and therapy. Leukemia. 1993
Apr;7(4):653-8
Oda T, Heaney C, Hagopian JR, Okuda K, Griffin JD, Druker
BJ. Crkl is the major tyrosine-phosphorylated protein in
neutrophils from patients with chronic myelogenous leukemia.
J Biol Chem. 1994 Sep 16;269(37):22925-8
LaMontagne KR Jr, Flint AJ, Franza BR Jr, Pandergast AM,
Tonks NK. Protein tyrosine phosphatase 1B antagonizes
signalling by oncoprotein tyrosine kinase p210 bcr-abl in vivo.
Mol Cell Biol. 1998 May;18(5):2965-75
Enright H, McGlave PB. Chronic myelogenous leukemia. Curr
Opin Hematol. 1995 Jul;2(4):293-9
Brümmendorf TH, Holyoake TL, Rufer N, Barnett MJ, Schulzer
M, Eaves CJ, Eaves AC, Lansdorp PM. Prognostic implications
of differences in telomere length between normal and
malignant cells from patients with chronic myeloid leukemia
measured by flow cytometry. Blood. 2000 Mar 15;95(6):188390
Bazzoni G, Carlesso N, Griffin JD, Hemler ME. Bcr/Abl
expression stimulates integrin function in hematopoietic cell
lines. J Clin Invest. 1996 Jul 15;98(2):521-8
Ilaria RL Jr, Van Etten RA. P210 and P190(BCR/ABL) induce
the tyrosine phosphorylation and DNA binding activity of
multiple specific STAT family members. J Biol Chem. 1996
Dec 6;271(49):31704-10
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
This article should be referenced as such:
Turhan AG. t(9;22)(q34;q11) in CML. Atlas Genet Cytogenet
Oncol Haematol. 2000; 4(4):205-208.
208
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Mini Review
Thyroid: Papillary carcinoma
Marco A Pierotti
Istituto Nazionale dei Tumori, Dept. of Experimental Oncology, Via Venezian, 1 20133 Milan, Italy (MAP)
Published in Atlas Database: August 2000
Online updated version : http://AtlasGeneticsOncology.org/Tumors/PapilThyroidCarID5053.html
DOI: 10.4267/2042/37675
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
or numerical changes were observed. In particular, 9
cases showed recurrent structural changes including:
inv10(q11.2q21.2) in 5 tumors,
a t(10;17)(q11.2;q23) in two cases, and
a der(1) in the last two tumors.
Classification
Note
Papillary Thyroid Carcinomas (PTCs) derives from the
thyroid follicular cells, as the other type of welldifferentiated thyroid carcinomas, the follicular ones;
however these differentiated thyroid cancers are
regarded as different entities:
The follicular carcinoma, solitary and encapsulated, is
associated with endemic goiter, a diet with low iodine
intake and metastatizes almost exclusively via the
blood stream, often to bones.
The papillary carcinoma, on the contrary, is multifocal
and associated with a previous radiation exposure, high
iodine intake and metastatizes through lymphatic
spread to regional lymph-nodes.
Genes involved and proteins
Note
These abnormalities represent the cytogenetic
mechanisms which activate the receptor tyrosine kinase
(RTK) proto-oncogenes RET on chromosome 10 and
NTRK1 on chromosome 1, respectively.
The alternative involvement of the RET and NTRK1
tyrosine kinases receptors in the development of a
consistent fraction (45%) of PTCs has been
demonstrated.
Somatic
rearrangements,
both
intra
and
interchromosomal, of RET and NTRK1 produce
several forms of oncogenes.
In all cases, RET or NTRK1 tyrosine kinase (TK)
domains are fused to the amino-terminus of different
gene products. The latter have been defined as
'activating' genes.
Cytogenetics
Cytogenetics Morphological
Seventy cases of papillary thyroid carcinomas (PTCs)
have been reviewed, 51 of them displaying a normal
karyotype (73%). In 10 cases non recurrent structural
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
209
Thyroid: Papillary carcinoma
Pierotti MA
appears essential for the development and maintenance
of both the peripheral and central nervous systems.
RET
Location
10q11.2
Protein
The RET proto-oncogene codes for the tyrosine kinase
receptor of GDNF (Glial cell Derived Neurotrophic
Factor) and Neurturin (NTN); activation of RET by
GDNF or NTN has been shown to require one of two
accessory proteins, GDNFRa and GDNFRb.
Germinal mutations
Germline mutations of proto-RET result in human
diseases including familial medullary thyroid
carcinoma MTC, multiple endocrine neoplasia type 2A
and 2B (MEN2A and MEN2B) and Hirschsprung’s
disease.
Somatic mutations
RET is expressed in the thyroid by normal C cells and
their pathologic counterpart, medullary thyroid
carcinoma (MTC); moreover, RET expression can be
detected
in
normal
adrenal
medulla
and
pheochromocytomas.
TPM3
Location
1q22-23
TPR
Location
1q25
TFG
Location
3q12
Result of the chromosomal
anomaly
Hybrid Gene
Location
17q23
Note
The RET/PTC1 oncogene, represents the first example
of oncogene activation in solid tumors due to an
acquired chromosomal abnormality.
Description
RET/PTC1 is a chimeric transforming sequence
generated by the fusion of the TK domain of RET to
the 5' terminal sequence of the gene H4/D10S170; both
partners in the fusion have been localized to
chromosome 10q and their fusion is the molecular
event consequent to a paracentromeric inversion of
chromosome 10q, inv 10 (q11.2q21.2).
ELE1
Fusion Protein
Location
10q11
Oncogenesis
H4/D10S170 has been shown to display a coiled-coil
sequence which confers to the oncoprotein the ability to
form dimers, resulting in a constitutive activation of the
TK function.
H4/D10S170
Location
10q21
AKAP10 (subunit RI-a of Protein Kinase
A)
NTRK1
Location
1q22
DNA / RNA
The NTRK1 proto-oncogene encodes the high affinity
receptor for Nerve Growth Factor (NGF).
Protein
NTRK1 is primarily expressed in the nervous system.
Germinal mutations
Mice carrying a germline mutation that eliminates
NTRK1 show severe sensory and sympathetic
neuropathies, including the loss of neurons of the
dorsal root ganglia associated with nociceptive
functions, and most die within one month of birth;
interestingly, point mutations leading to the
inactivation of the NTRK1 receptor, have been
identified in patient with CIPA (Congenital
Insensitivity to Pain with Anhidrosis), an autosomalrecessive disorder characterized by absence of reaction
to noxious stimuli; thus NGF signalling via NTRK1
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Hybrid Gene
Note
A second example of RET activation is the RET/PTC2
oncogene; the cytogenetic analysis of one case of
RET/PTC2 positive carcinoma revealed that this
oncogene arises from a t(10;17)(q11.2;q23) reciprocal
translocation.
Description
In this case the rearrangement involved the gene of the
regulatory subunit RI-a of Protein Kinase A, which
maps to chromosome 17q23.
Fusion Protein
Oncogenesis
Interestingly, like the H4 gene, RI-a also contains a
dimerization domain and the construction of
RET/PTC2 mutants with deletions in RI-a, has
demonstrated that the formation of dimers is necessary
to express the activity of the oncogene.
210
Thyroid: Papillary carcinoma
Pierotti MA
rearrangement involving the same two genes, TPR and
NTRK1, has been found in two other papillary thyroid
tumors; although the two rearrangements involve
different genomic regions of the partner genes, they
occur in the same intron of both TPR and NTRK1; as a
consequence, the same mRNA and 1323 aminoacid
oncoprotein are produced and designated TRK-T2 in
both cases; similarly to TRK-T1, the molecular
characterization of these rearrangements indicated the
chromosomal mechanism leading to the oncogenic
activation as an inv(1q).
Note
As for the last two oncogenes derived from NTRK1
activation, one is still uncharacterized whereas the
other, designated TRK-T3, has recently been analyzed.
Description
Sequence analysis revealed that TRK-T3 contains 1412
nucleotides of NTRK1 preceded by 598 nucleotides
belonging to a novel gene named TFG (TRK Fused
Gene) encoding a 68 kDa cytoplasmic protein; the
latter displays, in the TFG part, a coiled-coil region that
endows the oncoprotein with the capability to form
complexes, as shown by the TK domains; in this
condition, the latter can recruit SH2 and SH3
containing cytoplasmic effector proteins.
Hybrid Gene
Note
Finally, a third example of RET activation in PTCs has
been reported, RET/PTC3; also in this case, a
paracentric inversion of the long arm of chromosome
10 was identified.
Fusion Protein
Oncogenesis
In this oncogene, the TK domain of RET is fused to
sequences derived from a previously unknown gene
named ELE1 (otherwise named RFG). ELE1 is
localized in the same chromosomal region of RET,
10q11.2.
Hybrid Gene
Note
Several cases of PTCs showed an activation of the
NTRK1 proto-oncogene; in three specimens a chimeric
sequence generated by the rearrangement of an isoform
of non-muscle tropomyosin (TPM3) and NTRK1 was
identified; the former has been mapped to chromosome
1q22-23; therefore, the NTRK1 localization on 1q22
suggested that a 1q intrachromosomal rearrangement
could have generated the TRK oncogene.
Description
Molecular analysis of TRK positive PTCs revealed the
presence, not only of the product of the oncogenic
rearrangement (5'TPM3-3'NTRK1), but also of that
related to the reciprocal event (5'NTRK1-3'TPM3); this
finding indicates that an intrachromosomal inversion,
inv(1q), provided the mechanism of the NTRK1
oncogenic activation in these tumors.
Note
In the remaining cases genes different from TPM
provided the 5' terminus of the oncogene; therefore the
latter were designated as TRK-T.
Three cases showed the fusion of NTRK1-TK domain
to sequences of the TPR (Translocated Promoter
Region) gene, originally identified as part of the MET
oncogene.
Description
The first of these cases, TRK-T1, is encoded by a
hybrid mRNA containing 598 nucleotides of TPR and
1148 nucleotides of NTRK1; the TPR locus is on
chromosome 1q25; therefore, as for TRK, an
intrachromosomal rearrangement, molecularly defined
as an inversion of 1q, is responsible for its formation; a
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
To be noted
Note
In fact Ret/ptcs oncoproteins and in some cases Trk
oncoproteins were demonstrated to bind and activate
PLCg, an SH2-containing enzyme catalyzing the
hydrolisis of phosphatydilinositol biphospate to inositol
trophoshate and diacyl glicerol, and Shc, an adaptor
protein belonging to the Ras pathway; the
relocalization in the cytoplasm of RET and NTRK1
enzymatic activity could allow their interaction with
unusual substrata, perhaps modifying their functional
properties.
References
Ciampi R, Nikiforov YE. RET/PTC rearrangements and BRAF
mutations in thyroid tumorigenesis. Endocrinology. 2007
Mar;148(3):936-41
This article should be referenced as such:
Pierotti MA. Thyroid: Papillary carcinoma. Atlas Genet
Cytogenet Oncol Haematol. 2000; 4(4):209-211.
211
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Review
Bladder: transitional cell carcinoma
Jean-Loup Huret, Claude Léonard
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH), Cytogenetique, Laboratoire d'Anatomo Pathologie, CHU Bicetre, 78 r Leclerc, F94270 Le KremlinBicetre, France (CL)
Published in Atlas Database: October 2000
Online updated version : http://AtlasGeneticsOncology.org/Tumors/blad5001.html
DOI: 10.4267/2042/37676
This article is an update of:
Huret JL, Léonard C. Bladder: Transitional cell carcinoma. Atlas Genet Cytogenet Oncol Haematol.1999;3(4):205-206.
Huret JL, Léonard C. Bladder cancer. Atlas Genet Cytogenet Oncol Haematol.1997;1(1):32-33.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Bladder cancer: gross pathology: the bladder wall is massively infiltered by an ulcerated and hemorragic tumor. Courtesy Pierre
Bedossa.
Classification
Clinics and pathology
Note
Existence of different histologic types:
Transitional cell carcinoma of the bladder, herein
described,
Squamous cell carcinoma,
Adenocarcinoma (2%), rare,
Poorly differenciated carcinoma/small cell carcinoma,
exceptional.
Disease
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Cancer of the urothelium.
Epidemiology
Transitional cell carcinoma is the most frequent bladder
cancer in Europe and in the USA, representing 90-95%
of cases, while squamous cell carcinoma represents
212
Bladder: transitional cell carcinoma
Huret JL, Léonard C
Chromosome 3: implicated in 30%, mostly in complex
karyotypes; amplifications 3p21-24, 3q24 have been
found; del(3p) is associated with high grade/stage.
Chromosome 4: deletions in 20%, in particular in 4p16
and 4q13-23; amplification of 4q26 has been noted.
Chromosome 5: i(5p) occurs in 35% of cases.
Chromosome 6: del(6q) in 25%; may be correlated
with tumour invasion.
Chromosome 7: trisomy 7 is frequent in this cancer, as
well as in many other cancers, but also in normal
tissues; may still be of bad prognostic significance.
Chromosome 8: del(8p) in 25%; deletion of 8p12-pter,
8p22 in particular, may be associated with high
grade/stage; gains of 8q (especially 8q23-qter) may be
associated with tumour progression; however, C-MYC
(8q24) is rarely amplified.
Chromosome 9: monosomy 9 or deletions of
chromosome 9 are found in about 50% of cases; at
times found as the sole anomaly, demonstrating that it
is an early event, found equally in PTa stage and in
more advanced stages; not associated with a given
grade, and not correlated with P53 expression; it has,
however, recently been hypothezised that monosomy 9
could indicate a risk of recurrence; LOH appear to be
numerous within a given chromosome (e.g. LOH in
9p21, 9q22, 9q31-32, 9q33 and 9q34), but loci remain
to be precised, as reports are controversial;
homozygous deletions of CDKN2A/MTS1/P16 (9p21)
have been documented; LOH + mutation on the second
allele of CDKN2A are rare, but of significance;
CDKN2A is implicated in Pta stage but not in PTIS,
where P53 is found mutated;
CDKN2B/INK4B/P15 (9p21) is also implicated in a
small subset of cases; PAX5 (9p13) may be overexpressed in tumours; GSN (9q34) has a very low
expression in tumours in comparison with its
expression in normal bladder; LOH + mutation on the
second allele of TSC1 (9q33-34) has recently been
described.
Chromosome 10: del(10)(q23-25) has been noted;
PTEN (10q23), appears to be implicated in a very few
percentage of cases (homozygote deletion has been
found); Fas/APO1/CD95 (10q24): loss of one allele
and mutation in the second allele has been reported; a
hot-spot of mutations has been determined;
amplification 10q13-14 has been found.
Chromosome 11: monosomy 11 or del(11p) is found
in 20 to 50% of cases, more often in high grade and
invasive tumours, associated with tumour progression,
often found at the time of tetraploidisation; LOH in
11p15.1-p15.5; HRAS1 (11p15.5) is mutated in 15% of
cases; amplifications of 11q13-22 have been noted, but
would not be a prognostic factor.
Chromosome 12: del(12q) in 20%; amplification of
12q13-15 and/or 12q15-24 may be found.
Chromosome 13: del(13q) is found in 25% of cases;
correlated with high grade/stage; an altered Rb (13q14)
is expressed in 30 to 40% of tumours; these are high
only 5% in these countries, but up to 70-80% of cases
in the Middle East. Annual incidence: 250/106, 2% of
cancers, the fourth cancer in males, the seventh in
females, 3M/1F. Occurs mainly in the 6th-8th decades
of life. Risk factors: cigarette smoking and
occupational
exposure
(aniline,
benzidine,
naphtylamine); 20 to 30 years latency after exposure.
Clinics
Hematuria, irritation.
Pathology
Grading and staging: tumours are:
Graded by the degree of cellular atypia (G0->G3), and
Staged:
- pTIS carcinoma in situ (but high grade), and
- pTa papillary carcinoma, both mucosally confined;
- pT1 lamina propria invasive;
- pT2 infiltrates the superficial muscle, and
- pT3a, the deep mucle;
- pT3b invasion into perivesical fat;
- pT4 extends into neighbouring structures and organs.
Treatment
Resection (more or less extensive: electrofulguration -> cystectomy); chemo and/or radiotherapy, BCGtherapy.
Evolution
Recurrence is highly frequent.
Prognosis
According to the stage and the grade; pTa is of good
prognosis (> 90% are cured); prognosis is uncertain in
pT1 and G2 tumours, where cytogenetic findings may
be relevant prognostic indicators. 20% survival at 1
year (stable at 3 years) is found in T4 cases; however,
identification of individual patient's prognosis is often
difficult, although of major concern for treatment
decision and for follow up.
Cytogenetics
Cytogenetics Morphological
Highly complex: pseudo diploid karyotypes with only a
few abnormalities in early stages, evolving towards
pseudo-tetraploides hyper complexes karyotypes with
numerous unrecognizable markers in advanced stages;
pseudo-octoploidy may arise; the most frequent
anomaies are: +7, -9, -11 or del(11p), del(13q),
del(17p), and rearrangements of chromosomes 1, 5, and
10; monosomy 9 is a very early event, that may even
appear at the dysplastic stage; we will use indifferently
the terms deletion and loss of heterozygocity (LOH) for
chromosome regions, and preferably LOH for genes.
Chromosome 1: implicated in 35% of cases; mainly
del(1p); 1p22 and 1q31 are the most frequently
involved; amplification 1p32 has been noted; P73
(1p36) is often over-expressed.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
213
Bladder: transitional cell carcinoma
Huret JL, Léonard C
stage, invasive, and indicate a short survival; 90% of
tumours expressing Rb are invasives; disregulation of
the normal P16-Rb interactions have been documented,
with hyper expression of Rb and loss of function of
P16; amplification in 13q21-31 has been noted.
Chromosome 14: del(14q) in 25% of cases (especially
14q12 and 14q32); may be associated with tumour
progression.
Chromosome 17: del(17p) in 40% of cases; LOH are
mainly in 17p12-13, 17q11-22, and 17q 24-25;
del(17p) is a late event, mainly found in pT2 to pT4;
also found in a subset of pTIS, which might be a
relevant prognostic indicator for these tumours; P53
(17p13) alterations are correlated with grade and stage
(often PT3), and tumour progression; P53 is mutated in
more than 50% of high grade/stage tumours, and in
most PTIS; P53 is a prognostic factor: by high
grade/stage tumours, those expressing P53 are of a
worse prognosis; by low grade/stage, those not
expressing P53 are of better outcome; there is usually
LOH + mutation on the second allele of P53;
ERBB2/P185 (17q21) is expressed in high grade/stages
tumours, in metastases, and is associated with relapses;
NF1 (17q11) expression may be very low in tumours;
amplification of 17q22-23 has been noted.
Chromosome 18: del(18q) in 25%; associated with
high grade/stage; amplifications of 18q11 and 18q22
have been found.
Chromosome 22: amplification of 22q11-12 has been
noted.
Chromosome Y: Y loss in 30%; probably not
associated with stage, grade, Ki67, or P53 expression.
Other: double minute are found in high grades/stages;
multifocal tumours exhibit genomic instability; this
genomic instability is already present in normal tissus
and is increased in tumour tissus from the same
specimens, suggesting that a general genetic instability
is a reason for multifocality.
References
Cytogenetics Molecular
Coombs LM, Pigott DA, Sweeney E, Proctor AJ, Eydmann ME,
Parkinson C, Knowles MA. Amplification and over-expression
of c-erbB-2 in transitional cell carcinoma of the urinary bladder.
Br J Cancer. 1991 Apr;63(4):601-8
Gibas Z, Prout GR Jr, Connolly JG, Pontes JE, Sandberg AA.
Nonrandom chromosomal changes in transitional cell
carcinoma of the bladder. Cancer Res. 1984 Mar;44(3):125764
Wijkström H, Granberg-Ohman I, Tribukait B. Chromosomal
and DNA patterns in transitional cell bladder carcinoma. A
comparative cytogenetic and flow-cytofluorometric DNA study.
Cancer. 1984 Apr 15;53(8):1718-23
Smeets W, Pauwels R, Geraedts J. Chromosomal analysis of
bladder cancer: technical aspects. Cancer Genet Cytogenet.
1985 Apr 1;16(3):259-68
Babu VR, Lutz MD, Miles BJ, Farah RN, Weiss L, Van Dyke
DL. Tumor behavior in transitional cell carcinoma of the
bladder in relation to chromosomal markers and
histopathology. Cancer Res. 1987 Dec 15;47(24 Pt 1):6800-5
Fraser C, Sullivan LD, Kalousek DK. A routine method for
cytogenetic analysis of small urinary bladder tumor biopsies.
Cancer Genet Cytogenet. 1987 Nov;29(1):103-8
Smeets W, Pauwels R, Laarakkers L, Debruyne F, Geraedts J.
Chromosomal analysis of bladder cancer. II. A practical
method. Cancer Genet Cytogenet. 1987 Nov;29(1):23-7
Hopman AH, Poddighe PJ, Smeets AW, Moesker O, Beck JL,
Vooijs GP, Ramaekers FC. Detection of numerical
chromosome aberrations in bladder cancer by in situ
hybridization. Am J Pathol. 1989 Dec;135(6):1105-17
Vieillefond A, Quillard J, Ladouch-Badré A, Meduri G, Nenert
M, Matani A, Martin E. [Tumors of the bladder. The
pathologist's point of view]. Ann Pathol. 1989;9(4):249-64
Olumi AF, Tsai YC, Nichols PW, Skinner DG, Cain DR, Bender
LI, Jones PA. Allelic loss of chromosome 17p distinguishes
high grade from low grade transitional cell carcinomas of the
bladder. Cancer Res. 1990 Nov 1;50(21):7081-3
Perucca D, Szepetowski P, Simon MP, Gaudray P. Molecular
genetics of human bladder carcinomas. Cancer Genet
Cytogenet. 1990 Oct 15;49(2):143-56
Cairns P, Proctor AJ, Knowles MA. Loss of heterozygosity at
the RB locus is frequent and correlates with muscle invasion in
bladder carcinoma. Oncogene. 1991 Dec;6(12):2305-9
Flow cytometry for DNA index measurement has been
used in the past, but comparative genomic
hybridization (CGH) is now a major tool for deletions
and duplications determination; multi-FISH (M-FISH)
sould be very useful in early-stage cases (with pseudodiploid
karyotypes)
to
determine
structural
rearrangements.
Hemstreet GP 3rd, Rollins S, Jones P, Rao JY, Hurst RE,
Bonner RB, Hewett T, Smith BG. Identification of a high risk
subgroup of grade 1 transitional cell carcinoma using image
analysis based deoxyribonucleic acid ploidy analysis of tumor
tissue. J Urol. 1991 Dec;146(6):1525-9
Hopman AH, Moesker O, Smeets AW, Pauwels RP, Vooijs
GP, Ramaekers FC. Numerical chromosome 1, 7, 9, and 11
aberrations in bladder cancer detected by in situ hybridization.
Cancer Res. 1991 Jan 15;51(2):644-51
Genes involved and proteins
Note
The process 1- is multistep, 2- can take major and
minor routes, still to be determined; genes involved in
transitional cell carcinoma of the bladder are therefore
numerous and most are still unknown; some are quoted
above.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Moriyama M, Akiyama T, Yamamoto T, Kawamoto T, Kato T,
Sato K, Watanuki T, Hikage T, Katsuta N, Mori S. Expression
of c-erbB-2 gene product in urinary bladder cancer. J Urol.
1991 Feb;145(2):423-7
214
Bladder: transitional cell carcinoma
Huret JL, Léonard C
Presti JC Jr, Reuter VE, Galan T, Fair WR, Cordon-Cardo C.
Molecular genetic alterations in superficial and locally
advanced human bladder cancer. Cancer Res. 1991 Oct
1;51(19):5405-9
Xu HJ, Cairns P, Hu SX, Knowles MA, Benedict WF. Loss of
RB protein expression in primary bladder cancer correlates
with loss of heterozygosity at the RB locus and tumor
progression. Int J Cancer. 1993 Mar 12;53(5):781-4
Proctor AJ, Coombs LM, Cairns JP, Knowles MA. Amplification
at chromosome 11q13 in transitional cell tumours of the
bladder. Oncogene. 1991 May;6(5):789-95
Elder PA, Bell SM, Knowles MA. Deletion of two regions on
chromosome 4 in bladder carcinoma: definition of a critical
750kB region at 4p16.3. Oncogene. 1994 Dec;9(12):3433-6
Waldman FM, Carroll PR, Kerschmann R, Cohen MB, Field
FG, Mayall BH. Centromeric copy number of chromosome 7 is
strongly correlated with tumor grade and labeling index in
human bladder cancer. Cancer Res. 1991 Jul 15;51(14):380713
Herr HW. Uncertainty, stage and outcome of invasive bladder
cancer. J Urol. 1994 Aug;152(2 Pt 1):401-2
Sandberg AA, Berger CS. Review of chromosome studies in
urological tumors. II. Cytogenetics and molecular genetics of
bladder cancer. J Urol. 1994 Mar;151(3):545-60
Cordon-Cardo C, Wartinger D, Petrylak D, Dalbagni G, Fair
WR, Fuks Z, Reuter VE. Altered expression of the
retinoblastoma gene product: prognostic indicator in bladder
cancer. J Natl Cancer Inst. 1992 Aug 19;84(16):1251-6
Spruck CH 3rd, Ohneseit PF, Gonzalez-Zulueta M, Esrig D,
Miyao N, Tsai YC, Lerner SP, Schmütte C, Yang AS, Cote R.
Two molecular pathways to transitional cell carcinoma of the
bladder. Cancer Res. 1994 Feb 1;54(3):784-8
Milasin J, Mićić S. Cytogenetic evidence of gene amplification
in urothelial cancer--a possible mechanism of tumor
invasiveness. Urol Int. 1992;48(3):258-60
Wang MR, Perissel B, Taillandier J, Kémény JL, Fonck Y,
Lautier A, Benkhalifa M, Malet P. Nonrandom changes of
chromosome 10 in bladder cancer. Detection by FISH to
interphase nuclei. Cancer Genet Cytogenet. 1994 Mar;73(1):810
Cairns P, Shaw ME, Knowles MA. Preliminary mapping of the
deleted region of chromosome 9 in bladder cancer. Cancer
Res. 1993 Mar 15;53(6):1230-2
Chang WY, Cairns P, Schoenberg MP, Polascik TJ, Sidransky
D. Novel suppressor loci on chromosome 14q in primary
bladder cancer. Cancer Res. 1995 Aug 1;55(15):3246-9
Dalbagni G, Presti J, Reuter V, Fair WR, Cordon-Cardo C.
Genetic alterations in bladder cancer. Lancet. 1993 Aug
21;342(8869):469-71
Droller MJ. New efforts to stage bladder cancer. J Urol. 1995
Aug;154(2 Pt 1):385-6
Knowles MA, Shaw ME, Proctor AJ. Deletion mapping of
chromosome 8 in cancers of the urinary bladder using
restriction fragment length polymorphisms and microsatellite
polymorphisms. Oncogene. 1993 May;8(5):1357-64
Kallioniemi A, Kallioniemi OP, Citro G, Sauter G, DeVries S,
Kerschmann R, Caroll P, Waldman F. Identification of gains
and losses of DNA sequences in primary bladder cancer by
comparative genomic hybridization. Genes Chromosomes
Cancer. 1995 Mar;12(3):213-9
Meloni AM, Peier AM, Haddad FS, Powell IJ, Block AW, Huben
RP, Todd I, Potter W, Sandberg AA. A new approach in the
diagnosis and follow-up of bladder cancer. FISH analysis of
urine, bladder washings, and tumors. Cancer Genet
Cytogenet. 1993 Dec;71(2):105-18
Nemoto R, Nakamura I, Uchida K, Harada M. Numerical
chromosome aberrations in bladder cancer detected by in situ
hybridization. Br J Urol. 1995 Apr;75(4):470-6
Moch H, Sauter G, Moore D, Mihatsch MJ, Gudat F, Waldman
F. p53 and erbB-2 protein overexpression are associated with
early invasion and metastasis in bladder cancer. Virchows
Arch A Pathol Anat Histopathol. 1993;423(5):329-34
Orlow I, Lacombe L, Hannon GJ, Serrano M, Pellicer I,
Dalbagni G, Reuter VE, Zhang ZF, Beach D, Cordon-Cardo C.
Deletion of the p16 and p15 genes in human bladder tumors. J
Natl Cancer Inst. 1995 Oct 18;87(20):1524-9
Moore LE, Titenko-Holland N, Smith MT. Use of fluorescence
in situ hybridization to detect chromosome-specific changes in
exfoliated human bladder and oral mucosa cells. Environ Mol
Mutagen. 1993;22(3):130-7
Sarkis AS, Bajorin DF, Reuter VE, Herr HW, Netto G, Zhang
ZF, Schultz PK, Cordon-Cardo C, Scher HI. Prognostic value
of p53 nuclear overexpression in patients with invasive bladder
cancer treated with neoadjuvant MVAC. J Clin Oncol. 1995
Jun;13(6):1384-90
Sarkis AS, Dalbagni G, Cordon-Cardo C, Zhang ZF, Sheinfeld
J, Fair WR, Herr HW, Reuter VE. Nuclear overexpression of
p53 protein in transitional cell bladder carcinoma: a marker for
disease progression. J Natl Cancer Inst. 1993 Jan 6;85(1):53-9
Sauter G, Carroll P, Moch H, Kallioniemi A, Kerschmann R,
Narayan P, Mihatsch MJ, Waldman FM. c-myc copy number
gains in bladder cancer detected by fluorescence in situ
hybridization. Am J Pathol. 1995 May;146(5):1131-9
Sauter G, Moch H, Moore D, Carroll P, Kerschmann R, Chew
K, Mihatsch MJ, Gudat F, Waldman F. Heterogeneity of erbB-2
gene amplification in bladder cancer. Cancer Res. 1993 May
15;53(10 Suppl):2199-203
Sauter G, Moch H, Carroll P, Kerschmann R, Mihatsch MJ,
Waldman FM. Chromosome-9 loss detected by fluorescence in
situ hybridization in bladder cancer. Int J Cancer. 1995 Apr
21;64(2):99-103
Schapers RF, Ploem-Zaaijer JJ, Pauwels RP, Smeets AW, van
den Brandt PA, Tanke HJ, Bosman FT. Image cytometric DNA
analysis in transitional cell carcinoma of the bladder. Cancer.
1993 Jul 1;72(1):182-9
Sauter G, Moch H, Wagner U, Novotna H, Gasser TC,
Mattarelli G, Mihatsch MJ, Waldman FM. Y chromosome loss
detected by FISH in bladder cancer. Cancer Genet Cytogenet.
1995 Jul 15;82(2):163-9
Shipman R, Schraml P, Colombi M, Raefle G, Ludwig CU.
Loss of heterozygosity on chromosome 11p13 in primary
bladder carcinoma. Hum Genet. 1993 Jun;91(5):455-8
Shackney SE, Berg G, Simon SR, Cohen J, Amina S,
Pommersheim W, Yakulis R, Wang S, Uhl M, Smith CA.
Origins and clinical implications of aneuploidy in early bladder
cancer. Cytometry. 1995 Dec 15;22(4):307-16
Smeets W, Schapers R, Hopman A, Pauwels R, Ramaekers F.
Concordance between karyotyping and in situ hybridization
procedures in the detection of monosomy 9 in bladder cancer.
Cancer Genet Cytogenet. 1993 Nov;71(1):97-9
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Tanaka M, Müllauer L, Ogiso Y, Fujita H, Moriya S, Furuuchi K,
Harabayashi T, Shinohara N, Koyanagi T, Kuzumaki N.
215
Bladder: transitional cell carcinoma
Huret JL, Léonard C
Gelsolin: a candidate for suppressor of human bladder cancer.
Cancer Res. 1995 Aug 1;55(15):3228-32
interval on chromosome arm 8q. Genes Chromosomes
Cancer. 1998 Oct;23(2):167-74
Voorter C, Joos S, Bringuier PP, Vallinga M, Poddighe P,
Schalken J, du Manoir S, Ramaekers F, Lichter P, Hopman A.
Detection of chromosomal imbalances in transitional cell
carcinoma of the bladder by comparative genomic
hybridization. Am J Pathol. 1995 Jun;146(6):1341-54
Cairns P, Evron E, Okami K, Halachmi N, Esteller M, Herman
JG, Bose S, Wang SI, Parsons R, Sidransky D. Point mutation
and homozygous deletion of PTEN/MMAC1 in primary bladder
cancers. Oncogene. 1998 Jun 18;16(24):3215-8
Erbersdobler A, Friedrich MG, Schwaibold H, Henke RP,
Huland H. Microsatellite alterations at chromosomes 9p, 13q,
and 17p in nonmuscle-invasive transitional cell carcinomas of
the urinary bladder. Oncol Res. 1998;10(8):415-20
Mao L, Schoenberg MP, Scicchitano M, Erozan YS, Merlo A,
Schwab D, Sidransky D. Molecular detection of primary
bladder cancer by microsatellite analysis. Science. 1996 Feb
2;271(5249):659-62
Halachmi S, Madjar S, Moskovitz B, Nativ O.. Genetic
alterations in bladder cancer. Cancer J 1998; 11: 86-88.
Saran KK, Gould D, Godec CJ, Verma RS. Genetics of bladder
cancer. J Mol Med. 1996 Aug;74(8):441-5
Hovey RM, Chu L, Balazs M, DeVries S, Moore D, Sauter G,
Carroll PR, Waldman FM. Genetic alterations in primary
bladder cancers and their metastases. Cancer Res. 1998 Aug
15;58(16):3555-60
Simoneau AR, Spruck CH 3rd, Gonzalez-Zulueta M, Gonzalgo
ML, Chan MF, Tsai YC, Dean M, Steven K, Horn T, Jones PA.
Evidence for two tumor suppressor loci associated with
proximal chromosome 9p to q and distal chromosome 9q in
bladder cancer and the initial screening for GAS1 and PTC
mutations. Cancer Res. 1996 Nov 1;56(21):5039-43
Kavaler E, Landman J, Chang Y, Droller MJ, Liu BC. Detecting
human bladder carcinoma cells in voided urine samples by
assaying for the presence of telomerase activity. Cancer. 1998
Feb 15;82(4):708-14
Stadler WM, Olopade OI. The 9p21 region in bladder cancer
cell lines: large homozygous deletion inactivate the CDKN2,
CDKN2B and MTAP genes. Urol Res. 1996;24(4):239-44
Simon R, Bürger H, Brinkschmidt C, Böcker W, Hertle L, Terpe
HJ. Chromosomal aberrations associated with invasion in
papillary superficial bladder cancer. J Pathol. 1998
Aug;185(4):345-51
Takle LA, Knowles MA. Deletion mapping implicates two tumor
suppressor genes on chromosome 8p in the development of
bladder cancer. Oncogene. 1996 Mar 7;12(5):1083-7
Tsutsumi M, Tsai YC, Gonzalgo ML, Nichols PW, Jones PA.
Early acquisition of homozygous deletions of p16/p19 during
squamous cell carcinogenesis and genetic mosaicism in
bladder cancer. Oncogene. 1998 Dec 10;17(23):3021-7
Voorter CE, Ummelen MI, Ramaekers FS, Hopman AH. Loss
of chromosome 11 and 11 p/q imbalances in bladder cancer
detected by fluorescence in situ hybridization. Int J Cancer.
1996 Jan 26;65(3):301-7
Aaltonen V, Boström PJ, Söderström KO, Hirvonen O,
Tuukkanen J, Nurmi M, Laato M, Peltonen J. Urinary bladder
transitional cell carcinogenesis is associated with downregulation of NF1 tumor suppressor gene in vivo and in vitro.
Am J Pathol. 1999 Mar;154(3):755-65
Chaturvedi V, Li L, Hodges S, Johnston D, Ro JY, Logothetis
C, von Eschenbach AC, Batsakis JG, Czerniak B.
Superimposed histologic and genetic mapping of chromosome
17 alterations in human urinary bladder neoplasia. Oncogene.
1997 May 1;14(17):2059-70
Adshead JM, Ogden CW, Penny MA, Stuart ET, Kessling AM.
The expression of PAX5 in human transitional cell carcinoma
of the bladder: relationship with de-differentiation. BJU Int.
1999 Jun;83(9):1039-44
Gibas Z, Gibas L. Cytogenetics of bladder cancer. Cancer
Genet Cytogenet. 1997 May;95(1):108-15
Habuchi T, Yoshida O, Knowles MA. A novel candidate tumour
suppressor locus at 9q32-33 in bladder cancer: localization of
the candidate region within a single 840 kb YAC. Hum Mol
Genet. 1997 Jun;6(6):913-9
Aveyard JS, Skilleter A, Habuchi T, Knowles MA. Somatic
mutation of PTEN in bladder carcinoma. Br J Cancer. 1999
May;80(5-6):904-8
Richter J, Jiang F, Görög JP, Sartorius G, Egenter C, Gasser
TC, Moch H, Mihatsch MJ, Sauter G. Marked genetic
differences between stage pTa and stage pT1 papillary bladder
cancer detected by comparative genomic hybridization. Cancer
Res. 1997 Jul 15;57(14):2860-4
Baud E, Catilina P, Bignon YJ. p16 involvement in primary
bladder tumors: analysis of deletions and mutations. Int J
Oncol. 1999 Mar;14(3):441-5
Benedict WF, Lerner SP, Zhou J, Shen X, Tokunaga H,
Czerniak B. Level of retinoblastoma protein expression
correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder
cancer. Oncogene. 1999 Feb 4;18(5):1197-203
Wagner U, Bubendorf L, Gasser TC, Moch H, Görög JP,
Richter J, Mihatsch MJ, Waldman FM, Sauter G. Chromosome
8p deletions are associated with invasive tumor growth in
urinary bladder cancer. Am J Pathol. 1997 Sep;151(3):753-9
Chi SG, Chang SG, Lee SJ, Lee CH, Kim JI, Park JH. Elevated
and biallelic expression of p73 is associated withprogression of
human bladder cancer. Cancer Res. 1999 Jun 15;59(12):27913
Bartlett JM, Watters AD, Ballantyne SA, Going JJ, Grigor KM,
Cooke TG. Is chromosome 9 loss a marker of disease
recurrence in transitional cell carcinoma of the urinary bladder?
Br J Cancer. 1998 Jun;77(12):2193-8
Czerniak B, Chaturvedi V, Li L, Hodges S, Johnston D, Roy
JY, Luthra R, Logothetis C, Von Eschenbach AC, Grossman
HB, Benedict WF, Batsakis JG. Superimposed histologic and
genetic mapping of chromosome 9 in progression of human
urinary bladder neoplasia: implications for a genetic model of
multistep urothelial carcinogenesis and early detection of
urinary bladder cancer. Oncogene. 1999 Feb 4;18(5):1185-96
Baud E, Catilina P, Boiteux JP, Bignon YJ. Human bladder
cancers and normal bladder mucosa present the same hot
spot of heterozygous chromosome-9 deletion. Int J Cancer.
1998 Sep 11;77(6):821-4
Bruch J, Wöhr G, Hautmann R, Mattfeldt T, Brüderlein S,
Möller P, Sauter S, Hameister H, Vogel W, Paiss T.
Chromosomal changes during progression of transitional cell
carcinoma of the bladder and delineation of the amplified
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Herr HW, Bajorin DF, Scher HI, Cordon-Cardo C, Reuter VE.
Can p53 help select patients with invasive bladder cancer for
bladder preservation? J Urol. 1999 Jan;161(1):20-2; discussion
22-3
216
Bladder: transitional cell carcinoma
Huret JL, Léonard C
Hornigold N, Devlin J, Davies AM, Aveyard JS, Habuchi T,
Knowles MA. Mutation of the 9q34 gene TSC1 in sporadic
bladder cancer. Oncogene. 1999 Apr 22;18(16):2657-61
Yokomizo A, Mai M, Tindall DJ, Cheng L, Bostwick DG, Naito
S, Smith DI, Liu W. Overexpression of the wild type p73 gene
in human bladder cancer. Oncogene. 1999 Feb 25;18(8):162933
Junker K, Werner W, Mueller C, Ebert W, Schubert J,
Claussen U. Interphase cytogenetic diagnosis of bladder
cancer on cells from urine and bladder washing. Int J Oncol.
1999 Feb;14(2):309-13
Zhao J, Richter J, Wagner U, Roth B, Schraml P, Zellweger T,
Ackermann D, Schmid U, Moch H, Mihatsch MJ, Gasser TC,
Sauter G. Chromosomal imbalances in noninvasive papillary
bladder neoplasms (pTa). Cancer Res. 1999 Sep
15;59(18):4658-61
Koo SH, Kwon KC, Ihm CH, Jeon YM, Park JW, Sul CK.
Detection of genetic alterations in bladder tumors by
comparative genomic hybridization and cytogenetic analysis.
Cancer Genet Cytogenet. 1999 Apr 15;110(2):87-93
Awata S, Sakagami H, Tozawa K, Sasaki S, Ueda K, Kohri K.
Aberration of chromosomes 8 and 11 in bladder cancer as
detected by fluorescence in situ hybridization. Urol Res. 2000
Jun;28(3):185-90
Lee SH, Shin MS, Park WS, Kim SY, Dong SM, Pi JH, Lee HK,
Kim HS, Jang JJ, Kim CS, Kim SH, Lee JY, Yoo NJ.
Alterations of Fas (APO-1/CD95) gene in transitional cell
carcinomas of urinary bladder. Cancer Res. 1999 Jul
1;59(13):3068-72
Böhm M, Kleine-Besten R, Wieland I. Loss of heterozygosity
analysis on chromosome 5p defines 5p13-12 as the critical
region involved in tumor progression of bladder carcinomas. Int
J Cancer. 2000 Mar 20;89(2):194-7
Mahdy E, Yoshihiro S, Zech L, Wester K, Pan Y, Busch C,
Döhner H, Kallioniemi O, Bergerheim U, Malmström PU.
Comparison
of
comparative
genomic
hybridization,
fluorescence in situ hybridization and flow cytometry in urinary
bladder cancer. Anticancer Res. 1999 Jan-Feb;19(1A):7-12
Brennan P, Bogillot O, Cordier S, Greiser E, Schill W, Vineis P,
Lopez-Abente G, Tzonou A, Chang-Claude J, Bolm-Audorff U,
Jöckel KH, Donato F, Serra C, Wahrendorf J, Hours M,
T'Mannetje A, Kogevinas M, Boffetta P. Cigarette smoking and
bladder cancer in men: a pooled analysis of 11 case-control
studies. Int J Cancer. 2000 Apr 15;86(2):289-94
Neuhaus M, Wagner U, Schmid U, Ackermann D, Zellweger T,
Maurer R, Alund G, Knönagel H, Rist M, Moch H, Mihatsch MJ,
Gasser TC, Sauter G. Polysomies but not Y chromosome
losses have prognostic significance in pTa/pT1 urinary bladder
cancer. Hum Pathol. 1999 Jan;30(1):81-6
Choi C, Kim MH, Juhng SW, Oh BR. Loss of heterozygosity at
chromosome segments 8p22 and 8p11.2-21.1 in transitionalcell carcinoma of the urinary bladder. Int J Cancer. 2000 May
15;86(4):501-5
Ohgaki K, Iida A, Ogawa O, Kubota Y, Akimoto M, Emi M.
Localization of tumor suppressor gene associated with distant
metastasis of urinary bladder cancer to a 1-Mb interval on
8p22. Genes Chromosomes Cancer. 1999 May;25(1):1-5
Czerniak B, Li L, Chaturvedi V, Ro JY, Johnston DA, Hodges
S, Benedict WF. Genetic modeling of human urinary bladder
carcinogenesis. Genes Chromosomes Cancer. 2000
Apr;27(4):392-402
Pycha A, Mian C, Hofbauer J, Brössner C, Haitel A, Wiener H,
Marberger M. Multifocality of transitional cell carcinoma results
from genetic instability of entire transitional epithelium.
Urology. 1999 Jan;53(1):92-7
Louhelainen J, Wijkström H, Hemminki K. Allelic losses
demonstrate monoclonality of multifocal bladder tumors. Int J
Cancer. 2000 Aug 15;87(4):522-7
Richter J, Wagner U, Schraml P, Maurer R, Alund G, Knönagel
H, Moch H, Mihatsch MJ, Gasser TC, Sauter G. Chromosomal
imbalances are associated with a high risk of progression in
early invasive (pT1) urinary bladder cancer. Cancer Res. 1999
Nov 15;59(22):5687-91
Louhelainen J, Wijkström H, Hemminki K. Initiationdevelopment modelling of allelic losses on chromosome 9 in
multifocal bladder cancer. Eur J Cancer. 2000 Jul;36(11):144151
Muscheck M, Sükösd F, Pesti T, Kovacs G. High density
deletion mapping of bladder cancer localizes the putative
tumor suppressor gene between loci D8S504 and D8S264 at
chromosome 8p23.3. Lab Invest. 2000 Jul;80(7):1089-93
Simoneau M, Aboulkassim TO, LaRue H, Rousseau F, Fradet
Y. Four tumor suppressor loci on chromosome 9q in bladder
cancer: evidence for two novel candidate regions at 9q22.3
and 9q31. Oncogene. 1999 Jan 7;18(1):157-63
Salem C, Liang G, Tsai YC, Coulter J, Knowles MA, Feng AC,
Groshen S, Nichols PW, Jones PA. Progressive increases in
de novo methylation of CpG islands in bladder cancer. Cancer
Res. 2000 May 1;60(9):2473-6
Stacey M, Matas N, Drake M, Payton M, Fakis G, Greenland J,
Sim E. Arylamine N-acetyltransferase type 2 (NAT2),
chromosome 8 aneuploidy, and identification of a novel NAT1
cosmid clone: an investigation in bladder cancer by interphase
FISH. Genes Chromosomes Cancer. 1999 Aug;25(4):376-83
This article should be referenced as such:
Thygesen P, Risch A, Stacey M, Fakis G, Giannoulis F, Takle
L, Knowles M, Sim E. Genes for human arylamine Nacetyltransferases in relation to loss of the short arm of
chromosome 8 in bladder cancer. Pharmacogenetics. 1999
Feb;9(1):1-8
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Huret JL, Léonard C. Bladder: transitional cell carcinoma. Atlas
Genet Cytogenet Oncol Haematol. 2000; 4(4):212-217.
217
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Bloom syndrome
Mounira Amor-Guéret
Institut Curie - Section de Recherche, UMR 2027 CNRS, Batiment 110, Centre Universitaire, F-91405 Orsay
Cedex, France (MAG)
Published in Atlas Database: September 2000
Online updated version : http://AtlasGeneticsOncology.org/Kprones/BLO10002.html
DOI: 10.4267/2042/37677
This article is an update of: Huret JL. Bloom syndrome. Atlas Genet Cytogenet Oncol Haematol.1998;2(2):65-66.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Micronuclei (left); sister chromatid exchange (right) in a normal subject (herein: 19 SCE, instead of the hundred found in Bloom, see
below) - JL Huret.
Inheritance
Autosomal recessive; frequency is about 2/105
newborns in Ashkenazi Jews and in the Japanese
(founder effect: affected persons descent from a
common ancestor); much rarer otherwise.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Clinics
Note
168 cases have been registered in the Bloom's
syndrome Registry by James German; BS patients are
218
Bloom syndrome
Amor-Guéret M
predisposed to all types of cancer observed in the
general population; thus, BS is a model of initiation and
promotion of cancer, and highligths internal
causes/processes of cancers.
Carcinomas (of a wide variety) occur in 30 % of cases,
mainly after the age of 20 years.
Benign tumours (10%).
Evolution
Phenotype and clinics
Major medical complications apart from cancers are:
chronic lung disease, and diabetes mellitus (in 10 %).
- Phenotypic spectrum variable;
- Growth: dwarfism: intrauterine growth retardation;
birth weight: below 2.3 kg; mean length: 44 cm; adult
length < 145 cm;
- Skin: hyperpigmented (café au lait) spots;
hypopigmented areas; sun sensitive telangiectatic
erythema; in butterfly configuration across the face:
resembles lupus erythematous;
- Head: microcephaly; dolichocephaly; narrow face;
prominent nose and/or ears; characteristic high-pitched
voice;
- Normal intelligence;
- Immune deficiency --> frequent infections (may be
life-threatening);
- Other: myocardopathy; hypogonadism in male
patients; hypertriglyceridemia.
Prognosis
1/3 of patients are dead at mean age 24 years (oldest
died at 49 years, youngest died before 1 year), and the
mean age of the 2/3 remaining alive patients is 22 years
(range: 4-46 years).
Cytogenetics
Inborn conditions
Chromatid/chromosome
breaks;
triradial
and
quadriradial figures, in particular symetrical
quadriradial configuration involving homologous
chromosomes (Class I qr), which are pathognomonic
and which may be due to a mitotic crossing-over.
Diagnosis is on the (pathognomonic) highly elevated
spontaneous sister chromatid exchange rate (90 SCE
per cell; more than 10 times what is normally found); in
some persons a minor population of low SCE cells
exists, suggesting a recombination event between
maternal and paternal alleles (with different mutations),
giving rise to a wild type functional gene; this allowed
to localize the gene in a very elegant strategy.
Heterozygotes are not detectable by cytogenetic
studies.
Neoplastic risk
Nearly half of patients have had at least one cancer
(10% of whom having had more than one primary
cancer, which is quite characteristic of Bloom's); mean
age at first cancer onset: 25 years (range: 2-49 years):
Acute leukaemias (ALL and AML) in 15 % of cases;
lymphomas in 15 % as well; these occur mainly before
the thirties.
Sister chromatid exchange in a normal subject (left) and in a Bloom syndrome patient (right) - Mounira Amor-Guéret.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
219
Bloom syndrome
Amor-Guéret M
Other findings
Gorlin RJ, Cohen MM, Levin LS.. Syndromes of the head and
neck. Oxford Monogr Med Genet. 1990; 19: 297-300.
Note
Slowing of the cell cycle (lenthening of the G1 and S
phases).
Spontaneous mutation rate 10 times higher than normal
cells.
Ellis NA, Groden J, Ye TZ, Straughen J, Lennon DJ, Ciocci S,
Proytcheva M, German J. The Bloom's syndrome gene product
is homologous to RecQ helicases. Cell. 1995 Nov
17;83(4):655-66
Ellis NA, Groden J, Ye TZ, Straughen J, Lennon DJ, Ciocci S,
Proytcheva M, German J. The Bloom's syndrome gene product
is homologous to RecQ helicases. Cell. 1995 Nov
17;83(4):655-66
Genes involved and proteins
Ellis NA, German J. Molecular genetics of Bloom's syndrome.
Hum Mol Genet. 1996;5 Spec No:1457-63
Note
No complementation group.
Foucault F, Vaury C, Barakat A, Thibout D, Planchon P, Jaulin
C, Praz F, Amor-Guéret M. Characterization of a new BLM
mutation associated with a topoisomerase II alpha defect in a
patient with Bloom's syndrome. Hum Mol Genet. 1997
Sep;6(9):1427-34
BLM
Location
15q26.1
Protein
Description: 1417 amino acids; contains one ATP
binding site, one DEAH box, and two putative nuclear
localization signals.
Expression: Accumulates to high levels in S phase of
the cell cycle, persists in G2/M and sharply declines in
G1; hyperphoshorylated in mitosis.
Localisation: Nuclear.
Function: 3-5 DNA helicase; probable role in DNA
replication and repair.
Participates in a supercomplex of BRCA1-associated
proteins named BASC (BRCA1-Associated genome
Surveillance Complex).
Recombinant protein promotes ATP-dependent branch
migration of Holliday junctions.
Homology: Homology with the RecQ helicases.
Mutations
Germinal: Five BLM mutations introducing amino acid
substitutions and four BLM mutations introducing
premature nonsense codons into the coding sequence
have been described to date; one BLM mutation
consisting in a 6 bp deletion accompanied by a 7 bp
insertion at nucleic acid position 2281 is common in
patients from Ashkenazi Jewish ancestry, leading to a
truncated protein of 739 amino acids in length; the
mutated BLM protein is totally or partially is retained
in the cytoplasm, while the normal protein is nuclear.
German J. Bloom's syndrome. XX. The first 100 cancers.
Cancer Genet Cytogenet. 1997 Jan;93(1):100-6
Kaneko H, Orii KO, Matsui E, Shimozawa N, Fukao T,
Matsumoto T, Shimamoto A, Furuichi Y, Hayakawa S,
Kasahara K, Kondo N. BLM (the causative gene of Bloom
syndrome) protein translocation into the nucleus by a nuclear
localization signal. Biochem Biophys Res Commun. 1997 Nov
17;240(2):348-53
Karow JK, Chakraverty RK, Hickson ID. The Bloom's
syndrome gene product is a 3'-5' DNA helicase. J Biol Chem.
1997 Dec 5;272(49):30611-4
Barakat A, Ababou M, Onclercq R, Dutertre S, Chadli E, Hda
N, Benslimane A, Amor-Guéret M. Identification of a novel
BLM missense mutation (2706T>C) in a Moroccan patient with
Bloom's syndrome. Hum Mutat. 2000 Jun;15(6):584-5
Dutertre S, Ababou M, Onclercq R, Delic J, Chatton B, Jaulin
C, Amor-Guéret M. Cell cycle regulation of the endogenous
wild type Bloom's syndrome DNA helicase. Oncogene. 2000
May 25;19(23):2731-8
Karow JK, Constantinou A, Li JL, West SC, Hickson ID. The
Bloom's syndrome gene product promotes branch migration of
holliday junctions. Proc Natl Acad Sci U S A. 2000 Jun
6;97(12):6504-8
Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. BASC,
a super complex of BRCA1-associated proteins involved in the
recognition and repair of aberrant DNA structures. Genes Dev.
2000 Apr 15;14(8):927-39
This article should be referenced as such:
Amor-Guéret M. Bloom syndrome. Atlas Genet Cytogenet
Oncol Haematol. 2000; 4(4):218-220.
References
German J. Bloom's syndrome. I. Genetical and clinical
observations in the first twenty-seven patients. Am J Hum
Genet. 1969 Mar;21(2):196-227
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
220
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Short Communication
Simpson-Golabi-Behmel syndrome
Hope H Punnett
Genetics Laboratory, St. Christopher's Hospital for Children, Erie Avenue at Front Street, Philadelphia, PA
19134, USA (HHP)
Published in Atlas Database: September 2000
Online updated version : http://AtlasGeneticsOncology.org/Kprones/SimpsonGolabiID10038.html
DOI: 10.4267/2042/37678
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
References
Inheritance
X-linked with heterogeneity; most families map Xq26;
one large pedigree maps to Xp22.
David G. Integral membrane heparan sulfate proteoglycans.
FASEB J. 1993 Aug;7(11):1023-30
Hughes-Benzie RM, Pilia G, Xuan JY, Hunter AG, Chen E,
Golabi M, Hurst JA, Kobori J, Marymee K, Pagon RA, Punnett
HH, Schelley S, Tolmie JL, Wohlferd MM, Grossman T,
Schlessinger D, MacKenzie AE. Simpson-Golabi-Behmel
syndrome: genotype/phenotype analysis of 18 affected males
from 7 unrelated families. Am J Med Genet. 1996 Dec
11;66(2):227-34
Clinics
Phenotype and clinics
Pre-natal and post-natal overgrowth syndrome, similar
to Beckwith-Wiedemann syndrome.
Xq26: coarse facies with mandibular overgrowth, cleft
palate, heart defects, hernias, supernumerary nipples,
renal and skeletal abnormalities.
Xp22: lethal form, multiple anomalies, hydrops fetalis,
death within first 8 weeks of life with a neoplastic risk.
Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan P, Chen
EY, Huber R, Neri G, Cao A, Forabosco A, Schlessinger D.
Mutations in GPC3, a glypican gene, cause the SimpsonGolabi-Behmel overgrowth syndrome. Nat Genet. 1996
Mar;12(3):241-7
Lapunzina P, Badia I, Galoppo C, De Matteo E, Silberman P,
Tello A, Grichener J, Hughes-Benzie R. A patient with
Simpson-Golabi-Behmel
syndrome
and
hepatocellular
carcinoma. J Med Genet. 1998 Feb;35(2):153-6
Neoplastic risk
Wilms tumor, neuroblastoma during early childhood;
one case of hepatocellular carcinoma reported.
Brzustowicz LM, Farrell S, Khan MB, Weksberg R. Mapping of
a new SGBS locus to chromosome Xp22 in a family with a
severe form of Simpson-Golabi-Behmel syndrome. Am J Hum
Genet. 1999 Sep;65(3):779-83
Genes involved and proteins
Murthy SS, Shen T, De Rienzo A, Lee WC, Ferriola PC,
Jhanwar SC, Mossman BT, Filmus J, Testa JR. Expression of
GPC3, an X-linked recessive overgrowth gene, is silenced in
malignant mesothelioma. Oncogene. 2000 Jan 20;19(3):410-6
GPC3
Protein
Description: GPC3, an X-linked recessive overgrowth
gene, may encode a negative regulator of mesothelial
cell growth, based on observation that down-regulation
of GPC3 is a common occurrence in malignant
mesothelioma.
Function: Proteoglycans are essential cofactors in cellcell recognition systems, cell-matrix adhesion
processes and receptor-growth factor interactions.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Paine-Saunders S, Viviano BL, Zupicich J, Skarnes WC,
Saunders S. glypican-3 controls cellular responses to Bmp4 in
limb patterning and skeletal development. Dev Biol. 2000 Sep
1;225(1):179-87
This article should be referenced as such:
Punnett HH. Simpson-Golabi-Behmel syndrome. Atlas
Genet Cytogenet Oncol Haematol. 2000; 4(4):221.
221
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Cockayne syndrome
Claude Viguié
Service de Dermatologie, Hôpital Tarnier-Cochin, 89 rue d'Assas, 75006 Paris, France (CS)
Published in Atlas Database: October 2000
Online updated version : http://AtlasGeneticsOncology.org/Kprones/CockayneID10015.html
DOI: 10.4267/2042/37679
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Genes involved and proteins
Inheritance: Autosomal recessive.
Note
There is genetic heterogeneity in CS, giving rise to
complementation groups.
The genes involved are: CSA, also called ERCC8
(ERCC for Excision-Repair Cross Complementing
rodent repair deficiency) located on chromosome 5,
CSB, also called ERCC6 , located in 10q11-21; outside
CSA and CSB, there is: 3 patients who are XPB/CS,
involving XPB, also called ERCC3, located in 2q21; 2
patients XPD/CS, involving XPD, also called ERCC2,
located in 19q13; and 6 patients XPG/CS, involving
XPG, also called ERCC5, located in 13q32 (note: the
class of patients with both XP and CS were classified
earlier as CS III, but not anymore).
Clinics
Phenotype and clinics
Normal newborn; growth failure from the age of six
months; diagnosis from the age of two years on:
Senile appearance of the skin (pigmentation, atrophy)
with "mickey mouse" aspect (microcephaly, large ears,
large nose, deep set eyes).
"Senil dwarf" aspect in contrast with long limbs, large
hands and feet, cold fingers with cyanosis, flexion
contractures of joints.
Sensitivity to sunlight.
Severe encephalopathia with profond mental
retardation and sensory disorders (deafness, optic
atrophy).
Pigmentary retinitis leading to cecity.
Other disorders: hypertension, early atherosclerosis,
intracranial calcification, glomerulosclerosis.
References
Brosh RM Jr, Balajee AS, Selzer RR, Sunesen M, Proietti De
Santis L, Bohr VA. The ATPase domain but not the acidic
region of Cockayne syndrome group B gene product is
essential for DNA repair. Mol Biol Cell. 1999 Nov;10(11):358394
Neoplastic risk
Bartenjev I, Butina MR, Potocnik M. Rare case of Cockayne
syndrome with xeroderma pigmentosum. Acta Derm Venereol.
2000 May;80(3):213-4
No increased susceptibility to skin tumors and other
cancers, except for Cockayne syndrome expressing
xeroderma pigmentosum (XP) symptoms (association
with XPG, XPD or XPB group).
de Boer J, Hoeijmakers JH. Nucleotide excision repair and
human syndromes. Carcinogenesis. 2000 Mar;21(3):453-60
Evolution
Hanawalt PC. DNA repair. The bases for Cockayne syndrome.
Nature. 2000 May 25;405(6785):415-6
Clinical heterogeneity, but early death from cachexia
and dementia, early cutaneous tumors and
atherosclerosis.
Cytogenetics
Rockx DA, Mason R, van Hoffen A, Barton MC, Citterio E,
Bregman DB, van Zeeland AA, Vrieling H, Mullenders LH. UVinduced inhibition of transcription involves repression of
transcription initiation and phosphorylation of RNA polymerase
II. Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10503-8
Inborn conditions
This article should be referenced as such:
As in XP, the UV ligth-induced level of sister
chromatid exchange (SCE) is increased as well as the
rate of chromosome aberrations, mainly chromatid
breaks.
Viguié C. Cockayne syndrome. Atlas Genet Cytogenet Oncol
Haematol. 2000; 4(4):222.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
222
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in Oncology and Haematology
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Cancer Prone Disease Section
Short Communication
Trichothiodystrophy (TTD)
Claude Viguié
Service de Dermatologie, Hôpital Tarnier-Cochin, 89 rue d'Assas, 75006 Paris, France (CV)
Published in Atlas Database: October 2000
Online updated version : http://AtlasGeneticsOncology.org/Kprones/TrichothioID10042.html
DOI: 10.4267/2042/37680
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Cytogenetics
Alias: Ichtyosis, brittle hair, intellectual impairment,
decreased fertility, and short stature syndrome (IBIDS)
Inheritance: Recessive autosomal.
Inborn conditions
No known chromosome abnormalities.
Genes involved and proteins
Clinics
Note
The DNA repair defect is found in 3 classes:
Patient with TTD-A group (low level of the TFIIH
transcription factor),
Patients mutated in the XPB gene (TTD/XPB),
involving XPB, also called ERCC3, located in 2q21;
and
All the other patients mutated in the XPD gene
(TTD/XPD), involving XPD, also called ERCC2,
located in 19q13.
Phenotype and clinics
Photosensitivity, Ichtiosys, Brittle hair, Intellectual
impairment, Decreased fertility, Short stature (PIBIDS
syndrome).
Photosensitivity is absent in 50% of cases (therefore
called IBIDS syndrome).
Neoplastic risk
This familial disease IS NOT a cancer prone disease
but it involves the same complementation groups as in
xeroderma pigmentosum and Cockayne syndrome
(XPD, XPB), and share defects in similar genes.
References
de Boer J, van Steeg H, Berg RJ, Garssen J, de Wit J, van
Oostrum CT, Beems RB, van der Horst GT, van Kreijl CF, de
Gruijl FR, Bootsma D, Hoeijmakers JH, Weeda G. Mouse
model for the DNA repair/basal transcription disorder
trichothiodystrophy reveals cancer predisposition. Cancer Res.
1999 Jul 15;59(14):3489-94
Prognosis
Depends on the DNA repair defect (photosensitivity:
XPD-ERCC2, XPB-ERCC3, TTD-A) and on the
transcription errors (other signs).
de Boer J, Hoeijmakers JH. Nucleotide excision repair and
human syndromes. Carcinogenesis. 2000 Mar;21(3):453-60
This article should be referenced as such:
Viguié C. Trichothiodystrophy (TTD). Atlas Genet Cytogenet
Oncol Haematol. 2000; 4(4):223.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
223
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Cancer Prone Disease Section
Mini Review
Werner syndrome
Mounira Amor-Guéret
Institut Curie - Section de Recherche, UMR 2027 CNRS, Batiment 110, Centre Universitaire, F-91405 Orsay
Cedex, France (MAG)
Published in Atlas Database: October 2000
Online updated version : http://AtlasGeneticsOncology.org/Kprones/WernerID10017.html
DOI: 10.4267/2042/37681
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Cytogenetics
Inheritance
Autosomal recessive; prevalence of carriers is as high
as 1 in 150 to 1 in 200; frequency is about 0.3/105
newborns in Japanese.
Inborn conditions
'Variegated translocation mosaicism': skin fibroblast
cell lines from WRN patients are usually composed of
one or several clones, each marked by a distinctive,
apparently balanced translocation.
Clinics
Other findings
Note
Uncommon disorder characterized by early onset of
geriatric diseases and described as a "caricature of
aging" or "progeria of adults".
Note
WS cells express constitutively high levels of
collagenase in vitro.
WS cells exhibit a mutator phenotype characterized by
extensive deletions: 8-fold higher average frequency of
6-thioguanine-resistant lymphocytes in Werner
syndrome patients than in sex- and age-matched normal
controls.
WS cells usually achieve only about 20 population
doublings versus approximately 60 in normal cells in
culture (WRN gene could be a 'counting' gene
controlling the number of times that human cells are
able to divide before terminal differentiation). Forced
expression of telomerase in Werner syndrome
fibroblasts confers extended cellular life span and
probable immortality.
Phenotype and clinics
Early onset of atherosclerosis, osteoporosis, diabetes
mellitus, scleroderma-like skin changes, especially in
the extremities, cataract, graying of the hair,
subcutaneous calcification, slender limbs, stocky trunk,
beaked nose and cancers of non-epithelial cell origin.
Neoplastic risk
Malignancy is found in approximately 10% of WRN
patients.
Excess of soft-tissue sarcomas, osteosarcomas, myeloid
disorders and benign meningiomas. In addition, the
Japanese have an excess of melanomas and follicular,
and anaplastic thyroid carcinomas.
Genes involved and proteins
Evolution
Complementation groups
No complementation group.
During the first decade of life, WS patients appear
normal: the first manifestation is lack of the adolescent
growth spurt.
In the twenties, WS patients develop bilateral ocular
cataract and premature graying of the hair.
In the thirties and forties, osteoporosis, type II diabete
mellitus, accelerated atherosclerosis, and cancer occur.
In the fourth and fifth decades, WS patients often
succumb to cardiovascular disease or cancer.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
WRN
Location
8p12
Protein
Description: 1432 amino acids; contains one ATP
binding site, one DEXH helicase box, one exonuclease
224
Werner syndrome
Amor-Guéret M
A, Schellenberg GD, Martin GM. Homozygous and compound
heterozygous mutations at the Werner syndrome locus. Hum
Mol Genet. 1996 Dec;5(12):1909-13
domain unique among known RecQ helicases in the Nterminal region, a nuclear localization signal in the Cterminus and a direct repeat of 27 amino acids between
the exonuclease and helicase domains.
Localisation:
Nuclear,
predominant
nucleolar
localization.
Function: 3'-5' DNA helicase; 3'-5' exonuclease;
functionally interacts with DNA polymerase delta
(POLD1), which is required for DNA replication and
DNA repair; functionally interacts with Ku, involved in
double strand DNA break repair by non-homologous
DNA end joining.
Homology: With the RecQ helicases.
Mutations
Germinal: All of the WRN mutations found to date
either create a stop codon or cause frameshifts that lead
to premature termination: not a single missense
mutation had been identified.
Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R,
Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J,
Schellenberg GD. Positional cloning of the Werner's syndrome
gene. Science. 1996 Apr 12;272(5259):258-62
Ogburn CE, Oshima J, Poot M, Chen R, Hunt KE, Gollahon
KA, Rabinovitch PS, Martin GM. An apoptosis-inducing
genotoxin differentiates heterozygotic carriers for Werner
helicase mutations from wild-type and homozygous mutants.
Hum Genet. 1997 Dec;101(2):121-5
Marciniak RA, Lombard DB, Johnson FB, Guarente L.
Nucleolar localization of the Werner syndrome protein in
human cells. Proc Natl Acad Sci U S A. 1998 Jun
9;95(12):6887-92
Ishikawa Y, Sugano H, Matsumoto T, Furuichi Y, Miller RW,
Goto M. Unusual features of thyroid carcinomas in Japanese
patients with Werner syndrome and possible genotypephenotype relations to cell type and race. Cancer. 1999 Mar
15;85(6):1345-52
References
Moser MJ, Oshima J, Monnat RJ Jr. WRN mutations in Werner
syndrome. Hum Mutat. 1999;13(4):271-9
Hoehn H, Bryant EM, Au K, Norwood TH, Boman H, Martin
GM. Variegated translocation mosaicism in human skin
fibroblast cultures. Cytogenet Cell Genet. 1975;15(5):282-98
Cooper MP, Machwe A, Orren DK, Brosh RM, Ramsden D,
Bohr VA. Ku complex interacts with and stimulates the Werner
protein. Genes Dev. 2000 Apr 15;14(8):907-12
Fukuchi K, Martin GM, Monnat RJ Jr. Mutator phenotype of
Werner syndrome is characterized by extensive deletions. Proc
Natl Acad Sci U S A. 1989 Aug;86(15):5893-7
Kamath-Loeb AS, Johansson E, Burgers PM, Loeb LA.
Functional interaction between the Werner Syndrome protein
and DNA polymerase delta. Proc Natl Acad Sci U S A. 2000
Apr 25;97(9):4603-8
Fukuchi K, Tanaka K, Kumahara Y, Marumo K, Pride MB,
Martin GM, Monnat RJ Jr. Increased frequency of 6thioguanine-resistant peripheral blood lymphocytes in Werner
syndrome patients. Hum Genet. 1990 Feb;84(3):249-52
Li B, Comai L. Functional interaction between Ku and the
werner syndrome protein in DNA end processing. J Biol Chem.
2000 Sep 15;275(37):28349-52
Faragher RG, Kill IR, Hunter JA, Pope FM, Tannock C, Shall
S. The gene responsible for Werner syndrome may be a cell
division "counting" gene. Proc Natl Acad Sci U S A. 1993 Dec
15;90(24):12030-4
Wyllie FS, Jones CJ, Skinner JW, Haughton MF, Wallis C,
Wynford-Thomas D, Faragher RG, Kipling D. Telomerase
prevents the accelerated cell ageing of Werner syndrome
fibroblasts. Nat Genet. 2000 Jan;24(1):16-7
Thweatt R, Goldstein S. Werner syndrome and biological
ageing: a molecular genetic hypothesis. Bioessays. 1993
Jun;15(6):421-6
This article should be referenced as such:
Amor-Guéret M. Werner syndrome. Atlas Genet Cytogenet
Oncol Haematol. 2000; 4(4):224-225.
Oshima J, Yu CE, Piussan C, Klein G, Jabkowski J, Balci S,
Miki T, Nakura J, Ogihara T, Ells J, Smith M, Melaragno MI,
Fraccaro M, Scappaticci S, Matthews J, Ouais S, Jarzebowicz
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
225
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Xeroderma pigmentosum
Claude Viguié
Service de Dermatologie, Hôpital Tarnier-Cochin, 89 rue d'Assas, 75006 Paris, France (CV)
Published in Atlas Database: October 2000
Online updated version : http://AtlasGeneticsOncology.org/Kprones/XerodermaID10004.html
DOI: 10.4267/2042/37682
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
C, D, E, F, G and 7 characterized genes). Intensity and
precocity of signs are dependent on the gene involved;
groups A, C, D and G are associated with a more
severe disease.
The same genes are implicated in two related diseases:
Cockayne syndrome (groups B, D and G) and
trichothiodystrophy (groups B and D).
Identity
Inheritance
Recessive autosomal; occurrence is favored by
consanguinity; frequency is 0.3/105 with large
geographical variations; higher frequenciy observed in
Tunisia (10/105, role of consanguinity) and in Japan
(1/105); rare in black people.
Neoplastic risk
Propensity to cutaneous tumors after sun exposure (risk
X 1000 to develop cancer on sun -exposed areas of the
skin): benign lesions, multiple basal cell carcinomas
and spinal carcinomas (occuring in 2 to 40 year old
patients, median age 8 yrs), malignant melanomas
slightly later than carcinomas (risk x 2000 compared to
normal population), rarely other skin tumors
(fibrosarcomas, angiosarcomas).
Propensity to various solid tumors (mainly brain
tumors, x 10 to 20 fold in comparison with general
population).
Treatment
Photoprotection; genetic counseling; treatment of
malignant tumors.
Evolution
Progressively increasing number of cutaneous, ocular
and other solid tumors; cutaneous atrophy with
numerous scars and aesthetic damage; skin
abnormalities comparable to what is clinically and
histologically observed with aging; blindness; severe
mental retardation.
Prognosis
2/3 death before adult age.
Clinics
Note
Xeroderma pigmentosum (XP) is caused by a defect in
nucleotide excision repair mechanisms; various clinical
aspects and intensity of signs are described according
to the gene involved (7 known complement groups) and
type of mutation.
Phenotype and clinics
Severe sun photosensitivity (poikilodermia): induced
precocious cutaneous lesions, concomitant to first sun
exposures, on the exposed areas (hands, arms, face);
dry skin, senile-like, cutaneous retractions (premature
aging of the skin).
Photophobia, often the first sign, before cutaneous
lesions; followed by bilateral cataract; increased risk of
ocular benign and malign tumors.
Neurological signs (14 to 40% of patients): mental
retardation,
pyramidal
syndrome,
peripheral
neuropathia; more severe central nervous system (CNS)
disorders are observed when mutations occur in XPA
DNA binding site.
Clinical heterogeneity: related to genetic heterogeneity
of the disease (7 known complementation groups A, B,
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
226
Xeroderma pigmentosum
Viguié C
Above: characteristic aspect of evolved lesions of the face in an XP patient. To be noted multiple scars of carcinomas and an aged
aspect of the skin with poikilodermia. Below: multiple basocellular carcinomas on the face of an XP patient. Thick arrow points to a recent
lesion, and thin arrow to a scar of an old lesion - Courtesy Daniel Wallach.
complementation groups (XPA to G) plus an additional
variant form, evidenced by somatic cell fusion
experiments.
The genes involved are: XPA, located in 9q22, XPB,
also called ERCC3 (ERCC for Excision-Repair Cross
Complementing rodent repair deficiency), located in
2q21, XPC, located in 3p25, XPD, also called ERCC2,
located in 19q13, XPE, located on chromosome 11
XPF, also called ERCC4, located in 19q13 XPG, also
called ERCC5, located in 13q32, and XPV, also called
Pol eta, and located in 6p12-21.
All XP genes are implicated in various steps of the
NER (nucleotide excision repair) system, except the XP
variant that is mutated in a mutagenic DNA polymerase
(POL H) able to bypass the UV-induced DNA lesions;
various alterations of the same gene may involve
various
phenotypes
Cockayne
syndrome
,
trichothiodystrophy).
Cytogenetics
Inborn conditions
Hypermutability after UV irradiation in cell cultures;
no
increased
of
spontaneous
chromosome
abnormalities in lymphocytes of fribroblastes; however,
after UV-exposure an increased number of sister
chromatid exchanges (SCE) and chromosome
aberrations are observed (mainly chromatid-type
abnormalities); fibroblasts express an increased
sensitivity to chemical mutagens; there is no
cytogenetic feature useful for XP diagnosis.
Genes involved and proteins
Note
The clinical and cytologic XP heterogeneity is the
consequence of the genetic heterogeneity: 7
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
227
Xeroderma pigmentosum
Viguié C
Cleaver JE. Common pathways for ultraviolet skin
carcinogenesis in the repair and replication defective groups of
xeroderma pigmentosum. J Dermatol Sci. 2000 May;23(1):1-11
References
Cleaver JE, Thompson LH, Richardson AS, States JC. A
summary of mutations in the UV-sensitive disorders:
xeroderma
pigmentosum,
Cockayne
syndrome,
and
trichothiodystrophy. Hum Mutat. 1999;14(1):9-22
de Boer J, Hoeijmakers JH. Nucleotide excision repair and
human syndromes. Carcinogenesis. 2000 Mar;21(3):453-60
Nakura J, Ye L, Morishima A, Kohara K, Miki T. Helicases and
aging. Cell Mol Life Sci. 2000 May;57(5):716-30
Riou L, Zeng L, Chevallier-Lagente O, Stary A, Nikaido O,
Taïeb A, Weeda G, Mezzina M, Sarasin A. The relative
expression of mutated XPB genes results in xeroderma
pigmentosum/Cockayne's syndrome or trichothiodystrophy
cellular phenotypes. Hum Mol Genet. 1999 Jun;8(6):1125-33
This article should be referenced as such:
Viguié C. Xeroderma pigmentosum. Atlas Genet Cytogenet
Oncol Haematol. 2000; 4(4):226-228.
van Steeg H, Kraemer KH. Xeroderma pigmentosum and the
role of UV-induced DNA damage in skin cancer. Mol Med
Today. 1999 Feb;5(2):86-94
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
228
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Deep Insight Section
Micronuclei : Pitfalls and Problems
John RK Savage
34 City Road, Tilehurst, Reading, RG31 5HB, UK (JRKS)
Published in Atlas Database: July 2000
Online updated version : http://AtlasGeneticsOncology.org/Deep/MicronucleiID20016.html
DOI: 10.4267/2042/37683
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
the frequency in new cells returns to the control (untreated) level.
It is logical to expect that there should be some
numerical relationship between the number of AF per
cell and the number of MN per cell derived from them.
On the assumption that this relationship is fairly
simple, MN scoring in interphase cells has been
proposed, and used, as a quick and easy substitute for
the more difficult and time-consuming metaphase
aberration analysis (Countryman and Heddle, 1976;
Heddle, 1973; Heddle, 1975; Muller and Streffer,
1994).
In the context of mutagen screening, or when purely
qualitative answers are required, this is to some extent
valid, and meaningful results can be obtained (Heddle,
1990; Muller and Streffer, 1994). However, the MN
system is full of pitfalls for the unwary and there are
many factors which conspire to uncouple any simple
relationship between AF and MN, making critical
quantitative work very difficult.
The purpose of this paper is to highlight some of the
MN-system problems, because, to appreciate them, will
help in the design of meaningful experiments and
applications, and in the interpretation of any results
obtained.
Introduction
Ionizing radiation and numerous chemical mutagens
cause structural chromosomal aberrations, many of
which are visible at the light-microscope level. There
are many types, and a complicated classification
(Savage, 1976), so that specialised knowledge and
training are required for reliable scoring. These
aberrations form the basis of a large amount of
radiobiological and DNA-repair theory and have many
practical uses in the fields of biological dosimetry,
clinical cytogenetics and environmental monitoring
(Heddle, 1990; Streffer et al., 1998).
A proportion of the aberrations (usually referred to as
"Asymmetrical events" or "Unstable aberrations"
(Carrano and Heddle, 1973; Savage, 1976)) give rise to
chromosome fragments without spindle attachment
organelles (kinetochores, centromeres). These are
termed "acentric fragments", (AF). When the cell
divides, some of these fragments are excluded from the
main daughter nuclei and form small extra nuclei
within the cytoplasm, either on their own, or in
conjunction with other fragments. Such "micronuclei"
(MN) can appear in the cytoplasm of either, or both,
daughter cells.
Depending on the origin of the excluded fragment, i.e.
the type of aberration from which it was derived, both,
or only one daughter cell will suffer genetic loss. In
some cases, the aberrations lead to mechanical
separation problems ("bridges") at anaphase as well as
fragment loss. These events will ultimately kill the cell,
though "death" (measured by cessation of division)
may not occur until 2-4 divisions have taken place.
With time, therefore, when an acute radiation dose, or
treatment with a very short-lived chemical clastogen
has been given, MN production ultimately ceases, and
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Factors which can influence the AF
Æ MN relationship
For convenience, I will group the factors that influence
the observed frequencies of MN derived from a given
frequency of AF under four broad headings:
- Production factors.
- Fragment-fate factors.
- Cell-kinetic factors.
- The time-displacement factor. Production factors.
229
Micronuclei : Pitfalls and Problems
Savage JRK
Figure 1 :
which contribute acentric fragments (AF) to form
micronuclei (MN). The diagram also indicates those
which produce compound fragments, i.e. composed of
segments from more than one chromosome/chromatid
and also those which produce mechanical separation
problems ("bridges") at anaphase.
Fragment loss leads to genetic imbalance and ultimate
cell death ; this may affect either one, or both daughter
cells. Since there is frequently more than one aberration
per cell, the probability of both daughters being
affected is increased.
Which kinds predominate will depend upon the kind of
cells used, the stage of the cell in the cycle when
exposed to the clastogen, and the clastogen used.
a) Fragment origin.
Following radiation, very few of the MN observed are
derived from lagging whole chromosomes, most come
from asymmetrical structural aberrations. In contrast,
most of the spontaneously occurring ones appear to
arise from whole chromosomes. This has been shown
by the application of kinetochore-specific probes to
micronuclei (Degrassi and Tanzarella, 1988; Fenech
and Morley, 1989; Tucker and Eastmond, 1990).
There is only one type of MN but many different kinds
of aberration can contribute to them. Figure 1
summarises the principal types of aberration which
produce AF.
The principal structural chromosomal aberrations
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
230
Micronuclei : Pitfalls and Problems
Savage JRK
Ionizing radiation can produce all the types of
structural change, but the vast majority of chemical
clastogens produce, primarily, only chromatid-types.
Some of the fragments are compound, containing
segments from more than one chromosome, others are
simple. Thus, the extent of genetic loss varies
considerably and may affect both daughters, or only
one.
b) MN Generation.
Only AF excluded from the daughter nuclei at
telophase can produce MN. Thus, cell division is a
necessary condition for their appearance, and the MN
frequency will be expected to increase with time after
treatment as more and more aberration-bearing cells
pass through mitosis. Exposure of a non- or very slowly
dividing cell population, or a treatment that inhibits cell
division, will mean that almost no MN are observed.
AF included in either daughter nucleus will duplicate
along with the rest of the genome during S-phase and,
if the cell divides again, will produce a second crop of
MN, the duplication of the initial included fragment
augmenting the observed frequency.
As mentioned above, neither fragment loss nor
mechanical separation problems at anaphase
necessarily kill the cell immediately (though the latter
usually precludes further divisions) so quite a few AFbearing cells divide 2 or 3 times before cessation
leading to a continuous, but eventually declining,
production of MN for some time after treatment.
In the majority of cell systems, both the absolute and
the relative frequency of the various forms of primary
aberrations vary as the cell transits the cycle.
Consequently, the generation of excluded AF (and
hence MN) will also fluctuate with time after treatment.
In addition to this, we have to remember that with most
clastogens, especially chemicals, a further crop of
primary aberrations can arise in later divisions from
unused long-lived lesions. These also will contribute
AF for MN.
Is it affected by the clastogen used ?
Is it dependent upon the dose? There is some evidence
that fragment exclusion falls as the dose of ionizing
radiation increases.
Finally, and importantly, is PI affected by any drug
used to interfere with the cytoskeleton, and
concomitant
cytokinesis?
As,
for
example,
cytochalasin-B (Fenech and Morley, 1985; Fenech and
Morley, 1986), which is now almost universally used to
overcome the generation/dilution problem discussed
below.
b) Sister-fragment separation.
Chromosome-type (pre-replication) AF are always
paired, whereas chromatid-type (post replication) AF
are mixed, but predominantly single (Figure 1). It is
assumed, especially for theoretical work, that all paired
fragments retain their adherence, and are transmitted to
MN as a unit pair (Braselmann et al., 1986; Carrano
and Heddle, 1973; Wakata and Sasaki, 1987). Recent
evidence from certain species indicates that this may
not always be the case (Das and Sharma, 1987), so that
in some systems, two MN may sometimes arise from
one AF pair.
c) Fragment coalescence.
As the number of AF per cell increases, so also does
the probability that one MN may contain several AF.
Cytoplasmic currents around the spindle apparatus can
lead to vortexes ("Sargasso Seas") where AF collect,
enhancing this probability. Thus, at higher clastogen
doses, any 1:1 AF:MN expectation breaks down.
Several authors have noted the paucity of multi-MN
cells and the tendency to under-dispersion of MN
between-cell distributions.
Cell-kinetic Factors.
a) Dilution.
"Once an MN, always an MN". For practical purposes,
MN, once formed, do not disappear for a long time,
even in cells that have lost the ability to divide. Nor, in
the vast majority of cases, do MN themselves divide,
although when present at mitosis, they occasionally
show "premature chromosome condensation" (PCC).
Since nearly all cells that carry AF have a limited life
span (~1-4 divisions), only a finite number of MN are
produced, and the cells that are carrying them will soon
be out-grown by "normal", non-AF producing, non-MN
bearing, cells which will progressively "dilute" the
observed MN/cell frequency.
This conflict between "generation" versus "dilution"
with time after treatment leads to a "humped" yieldtime curve, the profile of which is highly dosedependent (Brock and Williams, 1985; Roberts et al.,
1986). This means that often, there is no unique MN
frequency that can be set against a given dose, with
inevitable uncertainty in the shape of any doseresponse curve. Consequently, since the rate of
Fragment-fate factors.
a) The Inclusion probability, (PI).
The probability that an AF is included when the
daughter nuclei re-form after division (Savage, 1988).
The probability of exclusion, PE = (1.0 - PI). When PI
<1.0, which appears to be the universal condition, then
MN will form at successive divisions as outlined
above. There is no recorded case of PI = 0.
A number of pertinent questions need to be asked, and
answered, about PI :
Is it a constant ? In some cases the answer is "No". It
differs between cell type within species (fibroblasts
versus lymphocytes, (Savage, 1988)), and between
different species for the same cell type. Good
information is lacking on effects of cell age, of
karyotype composition, of fragment-size or of fragment
number.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
231
Micronuclei : Pitfalls and Problems
Savage JRK
generation and of dilution are both affected by kinetic
factors (see below), neither the peak frequency, nor the
integrated area under the yield time curve, are reliable
measures of damage. This is a problem all too familiar
to those who attempt quantitative work with chromatidtype aberrations (Savage and Papworth, 1991).
b) Mitotic delay and perturbation.
Every known clastogen disturbs the orderly progression
of cells towards division. The magnitude of the effect is
dose, time, and probably stage dependent. Obviously,
the changed cell-rates and orders will have a
pronounced effect on factors like "generation" and
"dilution" and, by changing the mixture of cells present
in the scored sample, this will affect the observed
frequency of MN.
c) Interphase "death".
The failure of a cell to reach the next mitosis after
treatment. Sometimes loosely equated with "apoptosis",
but this latter term should be reserved for the highly
specialised "programmed" interphase death having
certain well defined biomolecular characteristics.
Interphase "death" as a general term, does not
necessarily involve cessation of physiological activity,
or nuclear degeneration (as an example consider the
"feeder-layer" technique).
Interphase "death" is a regular feature of chemical
clastogens, and some cell types show it after ionizing
radiation (e.g. unstimulated lymphocytes). If extensive,
a severe reduction in MN production will result. The
phenomenon may not be random, affecting only certain
developmental phases, so some bias of the AF source
may be introduced.
A technical innovation, CytochalasinB.
The conflict between "generation" and "dilution" was
recognised fairly quickly and several protocols were
suggested to counteract it.
One obvious solution is to identify and confine scoring
to those cells that have divided once, and once only,
since the clastogen was given. This eliminates dilution
by the overgrowth of undamaged cells coming round
for the second time.
The most popular and widely used method to achieve
this, utilises a drug called Cytochalasin-B (Cyt-B)
(Fenech and Morley, 1985; Fenech and Morley, 1986;
Wakata and Sasaki, 1987). In the presence of this
compound at appropriate dilution (2-6 mg/ml) the
nucleus goes through mitosis, but the daughter cells fail
to separate, leading to a bi-nucleate cell. Obviously,
such cells must have divided once since Cyt-B was
added, and MN scoring can be confined to this sub-set.
Provided everything, apart from cell separation, is
normal, the frequency of (MN/binucleate-cell) will be
twice that which would have been found in oncedivided mononucleate-cells. The frequency of
binucleate-cells with MN will also be approximately
twice that of once-divided mononucleate-cells.
The use of Cyt-B is, of course, only a partial solution,
since we only collect the MN formed from one mitosis.
Therefore, any treatment effects, or modifications in PI
will be reflected in the observed MN frequency.
However, it is a very useful method now almost
universally used for micronucleus studies, and it has
helped to clear up a lot of the problems which plagued
the early work.
Cyt-B can be used in sequential "pulse" treatments to
collect cohorts of cells at different times after
treatment. This enables one to follow the generation
and the dilution at different times after treatment.
There is still a lot to learn about the action of Cyt-B.
Curiously, only a proportion of cells seems to be
trapped, irrespective of concentration; mononucleate
cells with MN are always contemporary with
binucleate ones. Some of the trapped cells will divide
again if treatment is prolonged, but spindles become
multipolar and there is much non-disjunction so such
cells are useless for longer-term MN studies.
The Time-displacement Factor.
This is probably the most frequently overlooked factor
when quantitative comparisons between AF and MN
are made (Savage, 1989).
It is the failure to remember that aberration frequencies
are determined at a point in time (usually after a short
colcemid metaphase accumulation) and are therefore
"instantaneous"
mean
frequencies.
Observed
frequencies of MN are, however, "running" means,
based on the cumulative number of MN derived from
all divisions antecedent to the time of sampling.
Now, an instantaneous-mean and a running-mean are
mathematically quite different things, and are not
readily comparable. One of the dramatic differences is,
that in sequential samples, significant fluctuations seen
in the former, are thoroughly damped in the latter, and
this effectively severs any meaningful relationship
between AF and MN.
Thus, for example, in simple ratio comparisons of
MN/AF, we need to remember that we are not
comparing like with like, and the derived relationship
can be wildly out. Predictable ratios exist only in the
simplest hypothetical populations (Savage, 1989).
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Chronic irradiation and chemical
treatments.
So far, we have viewed the problems of quantitative
work on the relations of AF and MN assuming an acute
dose of clastogen. If, however, a chronic dose is given either by prolonged exposure time, or by incorporating
a radioactive source into the nucleus, then we introduce
an additional set of problems. This is a particular
difficulty when chemical clastogens are used, as the
232
Micronuclei : Pitfalls and Problems
Savage JRK
Brock WA, Williams M. Kinetics of micronucleus expression in
synchronized irradiated Chinese hamster ovary cells. Cell
Tissue Kinet. 1985 May;18(3):247-54
majority of these are long-lived, and/or the molecules
and lesions persist within the cells producing additional
primary aberrations in subsequent cell generations. In
practice, it is almost impossible to give anything
approaching a clean acute treatment, as one can when
using external radiation.
There is much intra-nuclear change going on as the cell
transits the various phases of the mitotic cycle, so it is
not surprising that sensitivity to clastogen effects
(aberration type and frequency, mitotic delay and
perturbation, and probably effectiveness of repair)
varies from one stage to another. With chronic
treatment, each cell must "run the gauntlet" of these
changes whilst damage production and repair are taking
place, and the various effects will accumulate and
confound. The repair processes will be continually
busy, stretched and probably over-stretched, whilst the
cell is trying to cope with the continuous influx of
problems (rather like mending a leaking pipe whilst
someone is boring holes elsewhere!).
The overall effect is to introduce additional
perturbations, frequent (often selective) cell death, and
the conflict between "generation" and "dilution" will be
considerably modified. Quite likely, the yield-time
curve will have extra peaks and troughs and will not
reflect the true sensitivity situation within the
population.
We always have to remember that the observed
frequency of any event, with which we construct our
graphs, and from which we draw our inferences,
depends entirely upon the mixture of cells which is
present in the sample scored (Savage and Papworth,
1991). Changes in this cell mixture can produce effects
as profound as real treatment-induced changes. It often
requires much wisdom to tell the difference.
Fenech M, Morley AA. Measurement of micronuclei in
lymphocytes. Mutat Res. 1985 Feb-Apr;147(1-2):29-36
Braselmann H, Bauchinger M,
radiation induced chromosome
formulae for the determination
parameters of aberrations.
1986;25(4):243-51
Fenech M, Morley AA. Cytokinesis-block micronucleus method
in human lymphocytes: effect of in vivo ageing and low dose Xirradiation. Mutat Res. 1986 Jul;161(2):193-8
Roberts CJ, Morgan GR, Holt PD. A critical comparison of the
micronucleus yield from high and low LET irradiation of
plateau-phase
cell
populations.
Mutat
Res.
1986
May;160(3):237-42
Das BC, Sharma T. The fate of X-ray-induced chromosome
aberrations in blood lymphocyte culture. Mutat Res. 1987
Jan;176(1):93-104
Wakata A, Sasaki MS. Measurement of micronuclei by
cytokinesis-block method in cultured Chinese hamster cells:
comparison with types and rates of chromosome aberrations.
Mutat Res. 1987 Jan;190(1):51-7
Degrassi F, Tanzarella C. Immunofluorescent staining of
kinetochores in micronuclei: a new assay for the detection of
aneuploidy. Mutat Res. 1988 Oct;203(5):339-45
Savage JR. A comment on the quantitative relationship
between micronuclei and chromosomal aberrations. Mutat
Res. 1988 Jan;207(1):33-6
Fenech M, Morley AA. Kinetochore detection in micronuclei: an
alternative method for measuring chromosome loss.
Mutagenesis. 1989 Mar;4(2):98-104
Savage JR. Acentric chromosomal fragments and micronuclei:
the time-displacement factor. Mutat Res. 1989 Apr;225(4):1713
Heddle JA. Micronuclei in vivo. In: Mutation and the
environment, B. Mendelsohn ML and Albertini RJ (eds), WileyLiss, New York. 1990:185-94.
References
Tucker JD, Eastmond DA. Use of an antikinetochore antibody
to
discriminate
between
micronuclei
induced
by
aneuploidogens and clastogens. In: Mutation and the
environment, B. Mendelsohn ML and Albertini RJ (eds), WileyLiss, New York. 1990 :275-84.
Carrano AV, Heddle JA. The fate of chromosome aberrations.
J Theor Biol. 1973 Feb;38(2):289-304
Heddle JA. A rapid in vivo test for chromosomal damage.
Mutat Res. 1973 May;18(2):187-90
Heddle JA, Harris JW. Letter: Rapid screening of
radioprotective drugs in vivo. Radiat Res. 1975 Feb;61(2):3503
Savage JRK, Papworth DG. Excogitations about the
quantification of structural chromosomal aberrations. in:
Advances in mutagenesis research, 3. Obe G (ed), SpringerVerlag, Berlin. 1991:162-89.
Countryman PI, Heddle JA. The production of micronuclei from
chromosome aberrations in irradiated cultures of human
lymphocytes. Mutat Res. 1976 Dec;41(2-3):321-32
Müller WU, Streffer C. Micronucleus assays. In: Advances in
Mutagenesis Research. Obe G (ed), Springer-Verlag, Berlin.
1994:1-134.
Savage JR. Classification and relationships of induced
chromosomal structual changes. J Med Genet. 1976
Apr;13(2):103-22
Streffer C, Müller WU, Kryscio A, Böcker W. Micronucleibiological indicator for retrospective dosimetry after exposure
to ionizing radiation. Mutat Res. 1998 Aug 3;404(1-2):101-5
Buckton KE. Chromosome aberrations in patients treated with
X-irradiation for ankylosing spondylitis. In: Radiation-induced
Chromosome Damage in Man. Ishihara T and Sasaki M (eds)
Alan Liss, New York. 1983:491-511.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Schmid E. Cell survival and
aberrations. I. Derivation of
of transmission and survival
Radiat Environ Biophys.
This article should be referenced as such:
Savage JRK. Micronuclei : Pitfalls and Problems. Atlas Genet
Cytogenet Oncol Haematol. 2000; 4(4):229-233.
233
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Educational Items Section
Cancer Prone Diseases
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: July 2000
Online updated version : http://AtlasGeneticsOncology.org/Educ/Cancers_e.html
DOI: 10.4267/2042/37684
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
I.
CHROMOSOME INSTABILITY
SYNDROMES
II.
RETINOBLASTOMA / LIFRAUMENI SYNDROME
- Squeletal malformations, particularly radius axis
defects.
- Progressive bone marrow failure → bone marrow
aplasia.
Neoplastic risk:
- Myelodysplasia and acute non lymphocytic
leukemia: in 10% of cases; i.e. a 15000 fold
increased risk; other cancers (5%).
Cytogenetics:
- Spontaneous chromatid/chromosome breaks.
- Hypersensitivity to the clastogenic effect of DNA
cross-linking agents.
- Slowing of the cell cycle (G2/M transition).
Genes:
- 4 complementation groups; genes FACC, FA1
Ataxia Telangiectasia (AT)
Autosomal recessive; q2 = 1/40 000.
Clinics:
- Telangiectasia: facial region exposed to sunlight.
- Progressive cerebellar ataxia.
- Combined immunodeficiency → infections → 80%
of deaths.
Neoplastic risk:
- T-cell malignancies (a 70 fold and 250 fold increased
risks of leukaemia and lymphoma respectively) →
20% of deaths.
Cytogenetics:
- More than 10% ofs mitoses bear a chromosome
rearrangement in 7p14, 7q35, 14q11, or 14q32
(illegitimate
recombinations
between
immunoglobulin superfamilly genes Ig and TCR).
- Clonal rearrangements further occur → T-cell
malignancy.
- Lenthening of the cell cycle (slower S phase).
III. HAMARTO-NEOPLASTIC
SYNDROMES
I. CHROMOSOME INSTABILITY
SYNDROMES
A handfull of rare genetic diseases associate
chromosome instability, DNA replication and/or repair
anomalies, some shared clinical features, and an
increased risk of cancer. These diseases are
characterized by a high level of spontaneous chromatid
breaks and chromosome rearrangements, and/or a
hypersensitivity to clastogens (see an introduction to
chromosomal aberrations). The genes implicated in
these diseases are partly known and seem to have a role
in DNA repair and/or in the cell cycle regulation. If
lesions into DNA are not correctly repared, mutations
and rearrangements will accumulate, until, by chance,
one of these mutations results in the activation of an
oncogene or in the inactivation of the allele(s) of a
tumor suppressor gene. Whence, chromosome
instability syndromes are paradigmatic.
Fanconi Anemia (FA)
Autosomal recessive; q2 = 1/40 000.
Clinics:
- Growth retardation.
- Skin abnormalities: hyperpigmentation and/or café
au lait spots.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
234
Cancer prone diseases
Huret JL
autosomal dominantly inherited, due to rare events
multiplied by numerous cells and conditional
probabilities; Li-Fraumeni syndrome is a rare disease
discovered from epidemiological studies, and P53 is,
otherwise, THE gene involved in 50% of the cancers.
Both genes are involved in the cell cycle regulation and
arrest. If the cell cycle is not stopped until the
background lesions into DNA are correctly repared,
mutations and rearrangements will accumulate along
the cycles, until, by chance, one of these mutations
results in the activation of an oncogene or in the
inactivation of the allele(s) of a tumor suppressor gene.
Retinoblastoma
Cancer prone disease at increased risk of the cancer of
the retina called (also) retinoblastoma
- Embryonnic tumor of the neurectoderma.
- Appears most often in childhood.
- There are sporadic forms (with a negative familly
history) and hereditary forms.
- There are unilateral forms (mostly in the sporadic
cases) and bilateral forms (mainly in the hereditary
cases).
- Hereditary forms seem to be transmitted as an
autosomal dominant disease with a 90 % penetrance.
- Patients having a retinoblastoma have an increased
frequency of other cancers, in particular of
osteosarcoma and pinealoma.
- In a (very) few cases, a visible chromosome 13
deletion may be seen on the constitutionnal
karyotype, and, according to the lenght of the
deletion, the patients present with dysmorphic
features and mental impairment (as usual for
unbalanced constitutional anomalies), in addition to
the cancer(s) of the retina they have.
These features are unusual, and some appear
contradictory...
They will be explained by the two-step inactivation
mechanism, according to AG Knudson (1971): both
alleles of a tumor suppressor gene must be inactivated
to let the cancer develop.
- 1st event : deletion
• In a germ cell: hereditary form (therefore each of
the cells of the patient, in particular each of the
cells of each of the 2 eyes bear the deletion: that
will considerably increase the risk of multiple
retinoblastomas in 1 eye, or of bilateral
retinoblastoma: conditional probability P(1st
allele) X P(2nd allele) with the first proba
already = 1).
• or in a retinoblast: sporadic form.
- 2nd event: 2nd deletion: in a retinoblast (somatic
deletion).
- Finally: when homozygosity for inactivation is
reached → the tumor develops.
The gene is recessive; it however seems to be
transmitted as an autosomal dominant disease in
hereditary forms: the hereditary mutation, first event,
Radiosensitivity:
- High sensitivity to radiations and to radiomimetic
drugs.
Genes:
- Gene in 11q23: ATM probable role in DNA repair,
recombinaison, and in the cell cycle control.
Note: Heterozygous for AT may be at increased risk of
breast cancer.
Bloom Syndrome (BS)
Autosomal recessive; q2 = 2/100 000.
Clinics:
- Sun sensitive telangiectatic erythema.
- Dwarfismn.
- Normal intelligence.
- Combined immunodeficiency → infections.
Neoplastic risk
- Carcinomas (30%), lymphomas (25%), acute
lymphocytic and non lymphocytic leukemias (15 %
each), ...
- Mean age at first cancer onset: 21 yrs; more than one
cancer in a given patient.
Cytogenetics:
- Spontaneous chromatid breaks.
- Diagnosis on the highly elevated spontaneous sister
chromatid exchange rate (90 per cell).
- Slowing of the cell cycle (lenthening of the G1 and S
phases).
Gene:
- Gene BLM , codes for a DNA helicase.
Xeroderma pigmentosum (XP)
Autosomal recessive; q2 = 0,4/100 000.
Clinics:
- Sun sensitiviromic lesions → skin cancers.
- Photophobia.
- Neurologic features.
Neoplastic risk:
- Multiple cutaneous and ocular tumors as early as
from the age of 8 yrs (in sun exposed zones).
Cytogenetics:
- Normal level of breaks and chromatid exchanges.
- Hypermutability of the cells under UV irradiation.
Genes:
- 9 complementation groups. Genes ERCC (excision
repair cross complement) and XP (ex: XPAC):
mumerous and dispersed on various chromosomes;
role in DNA repair (helicases) and in the complex
repair/transcription factor.
II RETINOBLASTOMA
FRAUMENI SYNDROME
and
LI-
These two diseases are examples of the involvement of
tumor suppressor genes; they are also of interest for
various reasons; retinoblastoma mixes constitutional
and acquired chromosome features, the gene Rb is
autosomal recessive but the disease appears to be
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
235
Cancer Prone Diseases
Huret JL
- With: breast cancers, sarcomas, brain tumors,
leukemias, ...
- Inclusion criteria: 1 individual having a sarcoma and
at least 2 related persons with a sarcoma or a
carcinoma.
P53:
- Gene sitting in 17p13; 20 kb, 11 exons (1st exon is
non coding), mRNA of 3,0 kb.
- The protein presents a transactivation domain, a
DNA-binding domain, nuclear localization signals
and a tetramerization domain.
- Transcriptional regulator: in response to DNA
damage, P53 activates the transcription of genes
implicated in the cell-cycle arrest and genes
implicated in apoptosis; these activations allow either
the cells to repair DNA damage before entering
further in the cell cycle, or to be eliminated.
- P53 is the most frequently (50%) mutated gene in
cancers (with loss of fonction of the second allele)
(SOMATIC MUTATION = ACQUIRED ANOMALY).
- P53 is found mutated as an inborn condition in most
(but not all!) patients with the congenital genetic
disease named Li-Fraumeni syndrome (GERMINAL
MUTATION = CONSTITUTIONNAL ANOMALY).
has a probability 1/2 to be transmitted to the "patient".
If, by some means or other, the (second) somatic hit has
a probability close to 1, then, the resulting probability
to have a retinoblastoma will be 1/2 x 1 = 1/2, what is
characteristic of autosomal dominant transmission.
The somatic event's probability is close to 1 (the "some
means or other" above noted is the result of the low rate
of mutations multiplied by the great number of cells at
risk).
This somatic hit is produced either by:
- Loss of the normal chromosome 13 → monosomy
with only the deleted 13 (hemizygosity).
- Loss of the normal chromosome 13 and duplication
of the deleted 13 (homozygosity).
- Deletion within the normal 13 where `the important
gene' sits.
- Mutation (or any other kind of inactivation) of `the
important gene' present on the normal 13.
This gene has been called Rb, and belongs to the class
of tumor suppressor genes (earlier "antioncogenes"), as,
when they are normal and active, they prevent from
cancer.
Rb: gene sitting in 13q14; 180 kb, 27 exons, mRNA of
4,7 kb --;> P105 Rb protein: can form complexes with
nuclear oncogenes; phosphorylated in S and G2/M
phases of the cell cycle; unphosphorylated in G0 and
G1 and associated with E2F; anti proliferative activity.
LI-Fraumeni syndrome and P53
1/3 of the population will have a cancer;
Besides, exist familial cancers; more than a hundred
genetic diseases are accompanied with an increased
risk of cancers (either specific or pleiotropic).
In the general population, if a given person has a
cancer: → risk is increased by 2 or 3 in the family.
In certain types of familial cancers: → risk X 103 !
How to suspect an hereditary cancer:
- Too early in life;
- More than 1 cancer in 1 patient;
- Positive family history (other cancers, more than
usual, in the family).
In 1969 FP Li and JF Fraumeni define a syndrome :
- Autosomal dominant,
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
III HAMARTO-NEOPLASTIC
SYNDROMES
Hamartomas are localized tissue proliferations with
faulty differenciation and mixture of component
tissues; these diseases are heritable; hamartomas are
benign proliferations that have a potential towards
neoplasia; patients may also be at increased risk of
benign and malignant tumors of other tissues and
organs. The genes known so far are tumor suppressor
genes, but no common fonction has yet been
established.
This article should be referenced as such:
Huret JL. Cancer Prone Diseases. Atlas Genet Cytogenet
Oncol Haematol. 2000; 4(4):234-236.
236
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Educational Items Section
Embryology, Semiology, Dysmorphology
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: July 2000
Online updated version : http://AtlasGeneticsOncology.org/Educ/PolyEmbryoEng.html
DOI: 10.4267/2042/37685
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
at a side of the palm numbered from 1 to 14 (see
Figure).
T normally ends in 13.
transversality index = A+B+C+D = 27 on
the Figure.
On the fingers may be counted the number of ridges
from the center of the pattern to the triradius. (example
here: n = 4); in case of an arch, n=0. For the 10 fingers,
males have 140 - 145 ridges, and female have 120 - 130
ridges, according to the formula: n = 187 - (30 * no of
X) - (12 * no of Y); this may be very useful in the
Underground to determine the sex of the person next to
you, and to pass the time.
METACARPO- OR METATARSOPHALANGEAL ANOMALIES
NUMERICAL ANOMALIES:
- Polydactyly: existence of supernumerary fingers.
example: palmar and/or plantar hexadactyly
trisomy 13.
- Syndactyly: union of 2 or more fingers or toes
(more or less complete, only involving the skin or
with bone fusion).
SIZE ANOMALIES:
- Brachydactyly: short fingers. Various types
according to which phalanx is involved (e.g.
brachymesophalangy: short medial phalanx).
- Brachymetacarpy: short metacarp(s) (example:
in Turner syndrome).
SHAPE ANOMALIES:
Clinodactyly: bend of fingers (often the 5th, as
in trisomy 21).
Camptodactyly: irreductible flexion of the 2nd
phalanx on the 1st (without bone involvment).
HANDS
The palm is characterized by:
flexion creases: generated by mouvements of
the skin in relation to joints motility.
dermatoglyphics: dermal ridges on fingers, on
the palm, and on the planta.
CREASES:
-
fingers: 2 flexion creases for each finger
(except the thumb: only 1 crease).
finger-palm creases.
palm : 3 normal creases:
•
longitudinal radial crease (LRC in the
Figure).
•
proximal transverse crease (PTC).
•
distal transverse crease (DTC).
Fusion of (complete fusion or bridge between) the 2
transverse creases is called single transverse crease,
transverse palmar crease, or simian crease.
DERMATOGLYPHICS:
Triradius: point of convergence of ridges from 3
different directions. Normally, there is:
1 axial triradius: normally in t, close to the
wrist.
4 subdigital triradii (a.b.c.d.).
On the pad of the distal phalanx, sometimes
on thenar or hypothenar eminences, are triradii,
accompanied with the following patterns:
•
worl: 2 triradii.
•
loops and equivalents (ulnar or radial
orientated): 1 triradius.
•
arches: 0 triradius.
From each palmar triradius a, b, c, d, and t, is drawn the
3 lines separating the ridges at this convergence point.
The longest is the main line (-- A B C D & T), ending
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
-
237
Arachnodactyly: long and slender fingers.
Embryology, Semiology, Dysmorphology
Huret JL
As isolated signs, these anomalies are often transmitted
as autosomal dominant traits.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
238
Embryology, Semiology, Dysmorphology
Huret JL
FACE: Semiology and Embryology
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
239
Embryology, Semiology, Dysmorphology
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Huret JL
240
Embryology, Semiology, Dysmorphology
Huret JL
HEART: Embryology and Malformations
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
241
Embryology, Semiology, Dysmorphology
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Huret JL
242
Embryology, Semiology, Dysmorphology
Huret JL
GENITALIA:
Embryology
This article should be referenced as such:
Huret JL. Embryology, Semiology, Dysmorphology. Atlas
Genet Cytogenet Oncol Haematol. 2000; 4(4):237-243.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
243
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Educational Items Section
Trisomy 21
Jean-Loup Huret, Pierre-Marie Sinet
CNRS UMR 8602, Faculté de Médecine Necker Enfants Malades, Paris, Franc (JLH, PMS)
Published in Atlas Database: August 2000
Online updated version : http://AtlasGeneticsOncology.org/Educ/PolyTri21Eng.html
DOI: 10.4267/2042/37687
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
1,5 /1 000 births.
Sex ratio: 3 males/2 females.
Increased median maternal age (34 years).
Maximal trisomy 21 births from mothers aged:
•
28 yrs (but this is only because the maximal
birth rate is for this maternal age).
•
Around 37 yrs.
•
The risk increases with maternal age: <0.1%
below 30 yrs; between 0.1% and 1% at ages 30-40
(0.2% at 34 yrs, 0.5% at 38 yrs, 0.7% at 39 yrs);
>1% above 40 yrs (5% at 46 yrs, 15% at 50 yrs).
The most frequent viable chromosome disease.
Like other inborn autosomal chromosome diseases,
associates dysmorphia + psycho-motor delay, and
possible visceral malformations (found in more than
1/3 of cases); a medico-pedagogic care and follow up
must be undertaken.
I. EPIDEMIOLOGY
(A question on epidemiology would also include
recurrence risks according to the karyotypic findings:
see paragraph on the karyotype).
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
244
Trisomy 21
Huret JL, Sinet PM
mouth;
o
1 - Dysmorphic syndrome associating (to various
extend):
•
o
o
o
o
o
o
o
o
o
o
Evocative face +++:
Frequent microcephaly, short neck, flat
occiput and brachycephaly;
Moon-shaped face;
Flat nasal bridge;
"Socket" nostrils;
Hypertelorism (or pseudo-hypertelorism);
Epicanthus (regresse with age);
Upward slanting palpebral fissures;
Brushfield spots in the iris
(pathognomonic, detectable in blue eyes).
Macroglossia; glossitis exfoliativa
(geographic tongue); scrotal tongue at late
childhood and in adulthood;
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Mouth frequently open; frequently open
o
II. CLINICAL EXAMINATION
•
o
o
o
o
o
•
•
•
245
Narrow/ high arched palate; high arched
narrow palate;
Late appearing/malformed teeth
(numerical anomalies, agenesis of lateral
incisors...);
Hands and feet:
Short and broad;
Brachymesophalangia of the 2nd and 5th
fingers;
Clinodactyly of the 5th finger;
Flat feet;
First toe set apart from the others by a
gap, with a crease.
Dry skin, mottled skin (livedo), with frequent
infections around orifices.
Hyperlaxity of ligaments.
Frequent umbilical hernia.
Trisomy 21
Huret JL, Sinet PM
•
2 - Psycho-motor delay (constant):
•
•
•
o
o
o
o
•
o
o
Hypotonia +++ at birth (hold his head at 6
mths, sits at age 1 yr, walks at age 2 yrs).
The mental retardation, not obvious in the
infant, will soon become manifest.
Children's behaviour:
Affectionate, gentle, cheerful;
Language difficulties;
Like to play, to mime, to tidy up
meticulously;
Normal memory.
Seizures (in 3% to 9%, as compared to 1% in
the general population).
•
o
o
o
III. DIAGNOSIS: THE KARYOTYPE
Proves the diagnosis, allows/implicates a genetic
counseling:
Recurrence risk is about 1 % if the anomaly is de novo,
more if one of the parents is a translocation carrier.
3 - Dermatoglyphics:
Free and homogeneous trisomy 21 (92,5 %
•
Transverse palmar crease in 75% of cases.
Beware: it is also present in 1% of the general
population; therefore, out of 8 transverse
palmar creases at birth, 7 come from the
general population and only 1 from a Down
syndrome baby (1% risk X 699/700 births
versus 75% risk X 1/700 births): one MUST
NOT make a diagnosis of trisomy 21 on this
isolated sign and throw parents into a panic.
• Axial triradius in t" (in 75%).
• Transversality index > 30.
This association of signs implicates that visceral
malformations have to be searched for, as they can
burden the vital prognosis and impose that emergency
treatments be started.
of cases):
•
Sporadic (de novo) cases.
•
Role of maternal age (see above in
epidemiology).
•
Recurrence risk: 1 to 2 %.
•
Karyotype: 47,XY,+21 ou 47,XX,+21.
•
Due to meiotic non-disjunction:
o
Of maternal origin:
- lst division: 70 %
- 2nd division: 20 %
o
Of paternal origin:
- lst division: 5 %
- 2nd division: 5 %
Free trisomy 21 in mosaic (2,5 % of cases):
•
•
4 - Malformations (45% of cases):
•
o
o
o
o
•
o
o
•
o
o
o
o
o
o
Heart (40%):
Atrioventricular septal defect (10 %);
Ventricular septal defect (10 %);
Patent foramen ovale (5 %);
Persistence of ductus arteriosus (5
%)...
Digestive (10 %):
Duodenal stenosis (1/3 of duodenal
stenosis are found in trisomy 21patients);
Imperforate anus...
Ocular:
Cataract (congenital or acquired);
Astigmatism;
Myopia;
Strabismus;
Congenital glaucoma;
Nystagmus.
•
•
o
o
•
De novo or transmitted from a parental
translocation (being a balanced translocation in the
parent); genetic coonseling is especially needed in
the latter case.
•
Karyotype with 46 chromosomes; the extra
chromosome 21 is most often translocated with
another acrocentric (groupe D: 14, 13 or 15 or
groupe G: 21 or 22) chromosome; example: 46,
XY, t(14;21).
•
Genetic counseling and recurrence risk:
o
t(Dq;21q) et t(21q;22q)
of maternal origin: risk = 15 %
of paternal origin: risk = 5%
o
t(21q;21q): risk = 100 %:
either → trisomy 21
or → spontaneous miscarriage (monosomy 21).
o
Other:
Partial trisomy 21 (rare). →
(the segment responsible for most of the
syndrome/phenotype is band 21q22.3.
Hematologic:
‘Transient leukemoid reaction’ may occur
Sometimes with a relapse as acute leukemia
(lymphoblastic (ALL) or more frequently nonlymphoblastic (ANLL) leukemias; M7-ANLL
(megakaryocytic) is particularly frequent. Watch
the hypersensitivity to methotrexate.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Sporadic cases.
Karyotype: 46, XY / 47, XY,+21 or 46, XX /
47, XX,+21.
Post zygotic event (mitotic).
Most often, the phenotype is typical, at times
attenuated.
Trisomy 21 due to translocation:
5 - Other:
•
Immunological:
Tuberculine hyporeactivity;
Immune deficiency.
Metabolic:
Hyperuricemia;
Abnormal glycemia;
Increased TSH (frequent); hypo or hyper
thyroidy.
246
Trisomy 21
Huret JL, Sinet PM
Associated with other
chromosome anomalies (rare).
V. PROGNOSIS
•
IV. EVOLUTION
•
•
•
•
•
•
•
o
o
o
•
o
o
•
Statural delay (adult = 1,50 m); weight excess
(→ diet).
Voice becomes hoarse.
Pelade may appear.
Puberty is delayed but normal; poor libido;
Fecondity in the female (→ contraception).
Hypothyroidy, Basedow (→ T3, T4, TSH,
reverse T3 regular determination).
Mental development:
Intelligence quotient (IQ) = 50 (mean
(and median)); between 30 and 80; Gaussian
curve, as in the general population but with a
mean shift to 50 instead of 100; vary according
to age);
Social insertion: partly according to
the familial environment, the guidance and
reassurance that the family receives, and
according to the medical, paramedical, and
pedagogic cares instaured;
Psychomotor therapy from the age of
6 mths, kinesitherapy, orthophony latter; nursery
school, followed if possible by a class of
handicapped children within a normal primary
school; latter, school and professional school in
specialized institutions; apprenticeship, manual
professionnal activity; insertion into active life;
they must not stay at parents home, where they
would remain with a child status, and finally
where they would grow old faster as parents get
old.
Early aging:
Behaviour may suddenly switch from
that of a happy and sociable child to a sad,
inactive and inexpressive adult;
Risk of senile dementia (Alzheimer
disease).
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
•
Life expectancy, formerly poor, has greatly
increased, due to antibiotherapy and surgery.
Prognosis can be impaired by:
1 - The extreme susceptibility to infections.
2 - Malformations, cardiac malformations in
particular.
3 - Acute leukemia (in 1 % of trisomy 21
infants/children, i.e. 20 times more frequently
than in the general population).
Intellectual prognosis: (see evolution).
VI. TREATMENTS
•
•
•
•
•
•
•
•
•
•
Surgery in the case of malformation(s).
Antibiotherapy of infections; antifungal
treatment of athletic foot.
Medical-paramedical-pedagogic cares;
psychomotor therapy, kinesitherapy, orthophony.
Thyroid function repeated examinations (once
a year).
Ophtalmologic tests (watch the
hypersensitivity to atropine), auditive tests.
Cervical X-rays (cervical instability→ risk of
cervical vertebrae dislocation).
Flat foot (special shoes, tricycle are
recommended).
Flat dorsum (swimming recommended).
Keloid scars (surgery only when needed,
avoid plastic surgery).
Artistic creativity should be developed and
supported.
This article should be referenced as such:
Huret JL, Sinet PM. Trisomy 21. Atlas Genet Cytogenet
Oncol Haematol. 2000; 4(4): 244-247.
247
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Educational Items Section
Other Constitutional Chromosome Diseases
Jean-Loup Huret, Claude Léonard
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: August 2000
Online updated version : http://AtlasGeneticsOncology.org/Educ/PolyConstitAutreEngl.html
DOI: 10.4267/2042/37686
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
regions of imbalance had more deleterious effects,
while others induced only mild disturbances. The
critical segment is, in some instances, very narrow:
band q22.3 is responsible of most of the trisomy 21
phenotype; it may even be smaller: the 200 kb critical
segment in del(4p) syndrome. In the latter case, one has
even evoked the notion of "contiguous gene
syndrome".
Continuous genes syndrome: some Mendelian
inherited diseases have been known for long, and their
deleterious effect well described. It has happen that a
given patient had presented with the addition of
phenotypes from different inherited diseases. A well
known example is that of a patient with the addition of
Duchenne muscular dystrophy, chronic granulomatous
disease, retinitis pigmentosa, and Mc Leod syndrome.
This patient had a deletion in Xp21, where all these
genes map.
Cryptic rearrangements/imbalances: it is likely that
a percentage of chromosome imbalances remain
undetected and/or undetectable: some of these
imbalances are probably cause of major anomalies; the
location of the chromosome imbalance may not be
suspected if the phenotype is not reminiscent of a well
known syndrome; others cryptic imbalances may have
no, or slight effects, and will never be uncovered
(another bias of sampling!).
GENERAL COMMENTS
Imbalances concerning gonosomes are less
deleterious than those affecting autosomes; Imbalances
leading to an excess of gene dosage (i.e. duplications,
trisomies) are less deleterious than those resulting in a
deficit (i.e. deletions, monosomies).
Bias of sampling: the most deleterious chromosome
imbalances are not seen but result in early miscarriages;
miscarriages and stillbirths occur in other syndromes,
and only the less deleterious are compatible with life.
Some signs are characteristic of the disease. They are
due to a gene effect or to the combination of genes
effects. their association can be called a contiguous
gene syndrome (see below).
Other signs are aspecific of the region involved; they
are the result of general gene imbalance and/or cell
division disturbances, and may be found in many
chromosome
syndromes:
growth
retardation,
microcephaly, mental retardation, low set ears... can be
found in various disease with no gene similarity.
Type/contertype: trisomy 4p syndrome (not herein
described) exhibit some signs which are the opposite of
del(4p) syndrome (e.g. flat/high forehead, aplasic/large
glabella, prognatism/microretrognatism). In trisomy 4p,
genes located in 4p are in 3 sets, while in del(4p) these
genes are in only 1 set. This is an example of probable
gene dosage specific effects.
Haploinsufficiency: is a term used in case of a deleted
segment with deleterious effects; it means that the
remaining haploid set of gene(s) is insufficient to allow
a normal function.
Critical region: it was previously thought that a
trisomy phenotype was due to the global excess of the
extra chromosome (e.g. trisomy 21), and a deletion
syndrome to the haploinsufficiency of the whole
deleted segment. With the description of cases with
overlapping imbalances, it became clear that some
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
OTHER AUTOSOMES DISEASES
A - DELETION 4p (Wolf-Hirschhorn syndrome /
Pitt-Rogers-Dank syndrome)
•
Karyotype: deletion of band 4p16 gives full
phenotype; critical segment narrowed to 200 kb.
• Clinics:
o
hypotrophy, low birth weight: 2 kg.
248
Other Constitutional Chromosome Diseases
Huret JL, Leonard C
Increased parental age.
Normal pregnancy duration.
Life expectancy: frequently found in
early miscarriages, and in late miscarriages;
stillbirths are common, and babies often die in
the neonatal period; very few reach adulthood.
•
II. Clinics:
o
Microcephaly, receding forehead.
o
Microphtalmia/anophtalmia,
colobomata of the iris, cataract.
o
Arrhinencephaly, probocis.
o
Hypotelorism.
o
Scalp defect (in relation with neural
tube fusion defects).
o
Hare-lip / cleft palate.
o
Umbilical hernia: 1/3 of cases.
o
Genitalia: cryptorchidy in the male,
uterus bicornis (constant) and vagina duplex
(often) in the female.
o
Fingers in flexion position; postaxial
polydactyly 80 % (hands and feet); club foot;
dermatoglyphics: axial triradius in t"; thenar
pattern.
•
III. Malformations: constant, heavy, leading to
early death in most of the cases.
o
Central nervous system:
Arhinencephaly (50 %).
Hypoplasia of the corpus
callosum (20 %).
Hypoplasia of the frontal
lobe.
Spina bifida.
o
Ocular:
Micro/anophtalmia (90 %).
Coloboma.
Retinal dysplasia.
Luxation or absence of lens.
o
Cardiac (constant):
Ventricular septal defect.
Patent foramen ovale.
Persistence
of
ductus
arteriosus
Tetralogy of Fallot.
o
Renal (50 %):
Hydronephrosis.
Polykystic kidneys ...
o
Digestive (50 %):
Malrotation of the intestine.
Malformation
of
the
pancreas.
Gallbladder agenesis.
o
Bones:
Spina bifida.
Rib malformations.
• IV. Karyotype:
o
Most often free and homogenous
trisomy.
microcephaly, high forehead, large
glabella, broad nose in prolongation of the
eyebrows line: greek helmet aspect.
o
hypertelorism, ocular malformations,
hare-lip / cleft palate.
o
long, slender, manicured fingers.
• Malformations:
o
heart (50%).
o
ocular; in particular colobomata (25%).
• IQ = 20; seizures; often bedridden.
B - DELETION 5p (cri-du-chat syndrome)
•
Karyotype: deletion of 5p14-p15 most often;
critical segment narrowed to 5p15.2 (about 2
Mbases); the deletion is de novo in 85% of the
patients, and 15% are familial cases of parental
balanced rearrangement
•
Epidemiology: 0.02/1 000 births.
•
Clinics:
o
Typical high-pitched cry in the
newborn (like a kitten)
Microcephaly, round moon-shaped face, hypertelorism,
broad nasal bridge, downward slanting
o
palpebral fissures, and micrognathia;
growth retardation
o
Triradius axial in t'.
o
Hypotonia in the newborn; hyperactivity,
tantrums, destructive behaviour is frequent in the
adult; autistic-like features may be present;
heavy psychomotor retardation (IQ may be at
20).
• Malformations: rare.
C - TRISOMY 8 MOSAICISM
•
Epidemiology: sex ratio 3M/1F; increased
parental mean age.
•
Clinics:
o
High forehead, everted lower lip.
o
Discrete dysmorphia.
o
Dermatoglyphics: deep
palmar/plantar furrows.
•
Malformations: kyphoscoliosis, hemivertebrae
and other osteoarticular disorders.
•
I Q: 50 to 70 mainly; however, cases with
normal intelligence and no visible malformation
remain undetected.
D - TRISOMY 9p
• Karyotype: critical segment likely to be in
9p22-p24.
• Clinics: microcephaly, deeply set eyes, broad
nose.
• Malformations: rare.
• I Q = 50.
o
o
o
o
E - TRISOMY 13 (Patau syndrome)
•
I. Epidemiology:
o
0.1 / 1 000 births.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
249
Other Constitutional Chromosome Diseases
o
o
Huret JL, Leonard C
flexion crease of fingers; clenched fingers with
overlap of the 2nd and 5th onto the 3rd and 4th;
dermatoglyphics: frequency of arches.
•
III. Malformations: constant, heavy, leading to
early death in most of the cases.
o
Cardiac: constant.
Ventricular septal defect.
Patent foramen ovale.
Persistence of ductus
arteriosus
Valves anomaly, in
particular mitral valve
o
Renal (1/3): mostly horseshoe kidney,
hydronephrosis, polykystic kidneys, hyploplastic
kidneys.
o
Digestive: frequent; Meckel, anal
atresia; pancreas anomalies.
o
Brain
o
Bones: spina bifida, hemivertebrae,
absence of clavicle.
•
IV. Karyotype
o
Most often free and homogenous
trisomy.
o
Frequency of doubles aneuploidies and
mosaics.
Sometimes translocation t(13q 14q).
Sometimes mosaic trisomy.
F - DELETION 18p (Edwards syndrome)
•
Brachycephaly, ptosis, broad nose, irregular
teeth.
•
Kyphoscoliosis.
•
Holoprosencephaly (10%).
IQ = 50; may have psychiatric behaviour.
G - DELETION 18q
•
Karyotype: deletion of 18q21-qter most often;
critical segment maps to 18q23.
•
Clinics:
o
Severe hypotonia (frog-like).
o
Midface hypoplasia; carp-shaped
mouth.
o
Tapered fingers.
o
Hearing impairment
o
Growth retardation
•
Malformations:
o
Ocular: constant.
o
Osteoarticular.
o
Genitalia.
o
Variable IQ, from 30 to over 70.
H - TRISOMY 18
•
I. Epidemiology:
o
0.2 / 1 000 births.
o
Increased parental age.
o
Pregnancy duration is often prolonged.
o
Life expectancy: frequently found in
miscarriages; stillbirths are common, and babies
often die in the neonatal period; very few reach
adulthood.
•
II. Clinics:
o
Hydramnios; single umbilical artery
frequently.
o
Low birth weight: 2,3 kg.
o
Constant sign: hypoplasia of the first
branchial arch, which implicates:
→ Low set ears
→ Microretrognatism
o
Pierre Robin syndrome:
Microretrognathism,
Cleft palate,
Glossoptosis.
o
Microcephaly (40 %), dolichocephaly.
o
Short neck with excess of skin .
o
Faun-like ear.
o
Short thorax and sternum, making the
abdomen looking long.
o
Hernias: diaphragmatic, umbilical,
inguinal.
o
Cryptorchidism (30 %).
o
Clubfoot; irreducible flexion of
forearms; dysplastic nails, absence of distal
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
DYSGONOSOMIES AND RELATED
SYNDROMES
A - TURNER SYNDROME
In a few words, Turner syndrome (or Ullrich-Turner
syndrome) is a syndrome of growth retardation and
impuberism with frequent cardiovascular or renal
malformation, normal intelligence, due to a
chromosome imbalance: 45, X and variants.
•
I. Epidemiology:
o
0.4/1000 female births (but 20 % of
chromosome anomalies found in early
miscarriages, i.e. about 10% early miscarriages).
o
Due to the loss of the maternal
gonosome (a X) in 20-30% of cases, or of the
paternal gonosome (a X or a Y) in the remaining
70-80%.
•
II. Clinical ascertainment/examination:
The diagnosis can be evoked either:
o
In the newborn (from dysmorphia
and/or malformations), or:
o
In the girl (from growth retardation,
impuberism).
1 - Neo-natal form:
o
Prenatal (and postnatal) growth
retardation
o
Single umbilical artery frequently.
o
Bonnevie-Ullrich (BU) status
associating:
250
Other Constitutional Chromosome Diseases
Huret JL, Leonard C
Lymphoedema of hands and
feet (tough, non inflammatory, regressive at
age 2 yrs).
Excess of skin and webbed
skin on the nucha (pterygium colli). 1/3 of BU
are found in Turner syndrome, and 75 % of
Turner have a BU In the presence of this
symptomatology, a karyotype will be
undertaken and (cardiac, renal) malformations
will be searched for.
2 - In childhood or adolescence:
o
Small size (adult < 1,45 m).
o
Triangular shaped face, looks sad.
o
Hypertelorism.
o
Blepharoptosis.
o
Possible epicanthus.
o
Downward slanting palpebrale
fissures.
o
Short neck.
o
Pterygium colli in more than half
cases.
o
Low hair line.
o
High-arched palate.
o
Micrognatism.
o
Low set hears
o
Shield chest.
o
Widely spaced nipples.
o
Short 4th metacarpal.
o
Cubitus valgus (increased carrying
angle of the elbow).
o
Radius curvus (Madelung's
deformity).
o
Sinking of internal tibial plateau (sign
of Kosowizc in the adult).
o
Osteoporosis (and fracture increased
risk) above 45 yrs.
o
Multiple pigmented nevi; vitiligo
and/or café-au-lait spots.
o
Risk of keloid scars (surgery only
when needed, avoid plastic surgery).
o
Dermatoglyphics: number of digital
crests = 187 - (30 * X) - (12 * Y) (herein = 157).
o
Hypoplastic nails.
o
Infantile external genitalia.
o
Hypoplastic uterus.
o
Amenorrhea and sterility.
o
Absence of breast development.
o
Rare pubic pilosity.
o
Normal or subnormal intelligence;
the (slight) cognitive defects are limited to
visual-spatial/perceptual abilities, attention,
motor function, and nonverbal memory. May be
partly due to psycho-social suffering, but also to
genetic imbalances and their various
consequences (e.g. hormone deficiency).
Malformations:
o
Cardiovascular (20-30%): aortic
coarctation (10-15 %) which may lead to death
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
o
o
o
o
•
o
o
o
•
o
o
o
o
o
•
o
o
o
•
o
o
o
o
by dissection or rupture of the aorta; bicuspid
aortic valve; left superior vena cava, and other
malformations; in the presence of aortic
coarctation in a girl, a Turner syndrome must be
evoked.
Renal (40-50 %): horseshoe kidney,
hydronephrosis...
Congenitally dislocated hip, scoliosis
Sense-organs: deafness (impaired
hearing in up to 40%), myopia, cataract,
strabismus.
X linked recessive inherited traits
have the same frequency in Turner syndrome and
in the male, since they both have only 1 X; this
frequency is that of the allele (e.g. daltonism,
hemophilia, Duchenne de Boulogne
myopathy...).
III. Diagnosis: the karyotype:
45, X homogeneous: 55 % of cases.
Isochromosomes: i(Xp), i(Xq);
deleted chromosomes: del (Xp), del (Xq); rings:
r(x); mosaicisms... → phenotypes are more or
less evocative of Turner syndrome some patients
having been fertile.
Most of the phenotypic traits are due
to Xp deletion, and only ovarian failure is
consistently associated with Xq deletions.
IV. Assessments:
Ovarian failure (sex steroid
deficiency and amenorrhea).
Streak gonads (germinal cells regress
at the 3rd month in utero; biopsy is not needed).
Impaired glucose tolerance;
hypertension (20-30%).
Autoimmune thyroid disease (T4,
TSH, thyroid-antibody titer determinations).
X-rays (skeleton, urinary system,
heart).
V- Differential diagnosis:
Other disorders with BonnevieUllrich status.
Gonadic dysgenesia.
Other disorders with primary
amenorrhea; e. g.: XY females (sex reversal).
VI. Treatments:
Surgery of malformations.
Gonadectomy if a Y chromosome is
present in mosaic (neoplastic risk).
Growth hormone and oestrogens to
manage growth failure and to induce menarch
and secondary sexual characters and menarche
and to prevent osteoporosis.
Psychological support (sterility).
Comments: Genes implicated in the syndrome are
thought to be localised in the region of the
gonososomes which escape X inactivation; the various
clinical manifestations may either be due to
251
Other Constitutional Chromosome Diseases
Huret JL, Leonard C
High gonadotropins and low
testosterone plasma levels.
o
Azoospermia in most non-mosaic
cases; however, intratesticular residual foci of
spermatogenesis may occasionally be found, and
mature spermatozoa may permit paternity using
intracytoplasmic sperm injection.
o
Biopsy (not needed): seminiferous
tubes atrophia, Leydig hyperplasia.
Treatment: testosterone replacement therapy to correct
the androgen deficiency and to provide virilization; can
also has positive effects on mood and self-esteem.
haploinsufficiency of specific genes (in the
pseudoautosomal region of X), aneuploidy effects (e.g.
on meiosis), and/or fetal suffering from the
lymphoedema.
o
B - KLINEFELTER SYNDROME
In a few words, Klinefelter syndrome is a syndrome of
a normal or gynecoid male with normal intelligence or
mild retardation, infertility, and possible behaviour or
psychiatric problems, due to a chromosome imbalance:
47, XXY and variants.
•
I. Epidemiology:
o
1.5 /1 000 male births.
o
Increased maternal age.
o
The extra X comes more often from
the mother.
•
II. Clinical ascertainment/examination:
o
Wide variability in clinical
expression:
o
Rarely diagnosed in childhood (from
mental retardation or non specific anomalies of
genitalia),
o
More often at puberty (from
gynecomastia, small testes),
o
Or when consulting for infertility.
o
Physical aspect is often normal,
o
They may present with tallness and
macroskelia,
o
Or with gynecoidy (gynecoid obesity:
25 %; gynecomastia: 15-25 %; bi-trochanteric
diameter > bi-acromial diameter).
Normal penis.
Small, indolent testes.
Normal or rare, feminine
shaped pubic pilosity.
Libido diminished;
impotence at age 30 yrs is frequent.
Sterility.
Normal or moderately
delayed intellectual development.
Dyslexia/dysphasia and
frontal-executive dysfunction.
Psychiatric behaviour is not
rare.
o
50-fold increased risk of developing
breast cancer as compared to normal males (and
8 times less than in females, as the women’s risk
is 400 times that of men) (nearly 10% of breast
cancers in males are found in Klinelter patients).
•
III. Diagnosis: the karyotype:
o
47 XXY homogeneous: 80 % of
cases.
o
XXXY, XXXXY, XXYY: 10 %.
o
In mosaic: 5-10 % (may (rarely) be
fertile).
•
IV. Assessments:
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
C - FRAXA and FRAXE SYNDROMES
(Fragile Xq or fra(X)(q28))
•
o
o
•
o
o
o
o
o
o
o
o
o
o
o
•
o
252
I. Epidemiology:
FRAXA: 0.2 / 1 000 male births and
0.1 / 1 000 female births.
FRAXE: 0.02/ 1 000 male births.
II. Clinics:
The face reminds of the one found in
trisomy 8.
Macrocephaly.
High forehead.
Midface hypoplasia.
Large nasal root.
Prognathism.
Thick lips.
High palate.
Large, unfolded ears.
Macroorchidy.
Fertility is often normal.
III. Mental development and psychiatric
behaviour (paragraph written by Denis ReserbatPlantey):
In the male:
Mental retardation is mild to severe (mean
IQ = 50): from a delay in school training to the
impossibility to acquire writing and reading
skills. The Fragile Xq young child is often
hypotonic; in the more severe forms, a
psychomotor delay is already present (delay in
walking...).
Speech difficulties: delay language
appearance, dysarthria, omissions, mumblings,
echolalias (tendency to repeat the same
sentences and to ask the same questions).
Behaviour problems: anguish, attention
deficit, hyperactivity, impulsiveness, escape of
glance, resistance to change, aggressiveness,
self-mutilation, stereotypies (wings beating,
"flapping") and oddities. Sometimes all these
symptoms are present, and constitute an
autistic syndrome.
The various studies carried out among the
autists show that 5 to 7 % autists are Fragile
Xq.
Other Constitutional Chromosome Diseases
Huret JL, Leonard C
normal phenotype. Frequency of premutations in
the population is 2.5/1000.
•
Hyperexpansion of more than 200 repeats are
called full mutation; they are hypermethylated
(on cytosines; even on the active X); it is inherited
in an unstable manner, but also, the mutation is
unstable in the individual (somatic mutations).
•
Almost all males and half of females with the
full mutation exhibit the syndrome. It is milder in
females.
Notes:
•
Passage from the normal allele to premutation
as never been observed.
•
Passage from premutation to mutation
(unstability, or expansion through inheritance) is
only through transmission from a female carrier.
FRAXE
•
Locus in Xq27-q28, 600kb distal to FRAXA.
•
Identical process of hyperexpansion of CpG
islands.
•
Much milder phenotype.
Note: this type of unstable mutations has been found in
other diseases, such as Huntington disease, a
progressive neuropsychiatric disorder with CAG
repeats in 4p16.
o
In the female:
The mental retardation is mild or absent. They can
present with: school difficulties (less than in the boy),
memory disorders, changing mood, timidity, relational
difficulties, and depressive tendency. These symptoms
are often misinterpreted for social causes.
•
IV. Diagnosis: the karyotype can show
recurrent gaps in Xq27-q28; however, the
diagnosis now rely on the molecular study of the
genes.
FRAXA
•
The disease is due to the hyperexpansion of a
CGG trinucleotide repeats in the 5' untranslated
region of the gene FMR-1 (fragility, mental
retardation), located in Xq27.3.
•
As a consequence of their hyperexpansion,
these CpG islands become hypermethylated,
leading to shut down the FMR-1 gene expression.
•
The normal FMR-1 product is a protein called
FMRP, a RNA binding protein widely expressed,
in particular in the brain and the testis
•
In the normal population, the CGG repeat size
is variable, from 6 to 54 repeats; it is inherited in a
stable manner.
•
Some people have between 60 and 200
repeats; this is called premutation; it is inherited
in an unstable manner (you tend to have more
repeats than Mummy), but stable in the individual
(identical in each cell). Premutation carriers have a
o
D - 47, XXX
•
•
Epidemiology: 1 / 1 000 female births;
increased parental age.
Clinics:
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
o
o
253
Often undetected: a normal female
with normal phenotype, puberty, fertility, and
offspring (most often).
Precocious menopause.
Mild mental delay and/or psychosocial disturbances are sometimes found.
Other Constitutional Chromosome Diseases
Huret JL, Leonard C
E - 48, XXXX and 49, XXXXX
shortness and other common signs: this is why it is
herein cited. It is in fact an autosomal dominant
trait.
Cardiac malformations, mild mental
retardation, infertility or fertility.
A gene maps in 12q24.
•
Mimics trisomy 21; mental retardation.
•
F - 47, XYY
•
•
o
o
o
•
Epidemiology: 1 / 1 000 male births.
Clinics:
Often undetected: a normal but tall
male with a normal phenotype.
Fertility may be reduced; normal
offspring.
Mild mental delay can be present;
impulsivity, violence, and psychiatric behaviour
are not rare.
OTHER CHROMOSOME
IMBALANCES
A - TRIPLOIDY
•
G - XX MALE SYNDROME
•
•
•
Epidemiology: 0.1 / 1 000 male births.
Clinics: Klinefelter like phenotype; sterility.
Sex reversal can be due to the presence of
male determining sequences on a X chromosome
(from a X/Y interchange at paternal meiosis), or
on an autosome (from a Y/autosome translocation
in the father), in particular SRY (Sex determining
Region, Y chromosome). Other sex determining
genes, usually sitting on gonosomes or on
autosomes are likely to be involved.
•
•
H - XY FEMALE SYNDROME
•
•
•
B - TETRAPLOIDY
Epidemiology: 0.1 / 1 000 female births.
The phenotype is that of a female with ovarian
failure, and with or without other stigmata (e.g.
sexual anomalies, limbs anomalies).
Sex reversal in XY females can be due to
mutations in SRY in 15%, or to other known or
unknown genes mutations; some of these genes
map to autosomes (e.g. SOX9 on chromosome
17).
4N = 92 chromosomes. Found in 5 % of miscarriages.
Literature records very few live births, but with death
soon after.
This article should be referenced as such:
Huret JL, Léonard C. Other Constitutional Chromosome
Diseases. Atlas Genet Cytogenet Oncol Haematol. 2000;
4(4):248-254.
I - NOONAN SYNDROME
•
Formerly called Turner syndrome with a
normal karyotype (46, XX or 46, XY) from the
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Epidemiology: the most frequent chromosome
aberration in early miscarriages; found in 20 % of
spontaneous miscarriages. Stillbirths are also
frequent; livebirth can occur, but the baby dies
shortly afterwards.
Karyotype: 3N = 69 chromosomes: i.e. 69,
XXX, or 69, XXY, or rarely 69, XYY; due to a
fertilisation anomaly: digyny: non-expulsion of
the 2nd polar body; or diandry: fertilisation of 1
oocyte I by 2 spermatozoa. Diandry is 4 times
more frequent than digyny.
Clinics: Preeclampsia; large placenta, with
frequent hydatiform mole; severe growth
retardation; microcephaly; syndactily; heavy brain,
heart, kidney and ocular malformations leading to
death.
254
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Other Constitutional Chromosome Diseases
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
Huret JL, Leonard C
256