Excess of Rare Cancers in Werner Syndrome (Adult Progeria)

Transcription

Vol.
5. 239-246,
April
Excess
Makoto
Haruo
Goto,
Sugano2
Cancer
1996
Robert
of Rare
W.
Miller,’
Cancers
Yuichi
Ishikawa,
in Werner
(Adult
& Prevention
239
Progeria)
WRN,3
an autosomal
recessive
trait (MIM#27770)
characterized by features
of premature
aging,
is unusually
frequent
in
Japan
because
of previously
high rates of inbreeding
there.
Death
on average
is at 47 years,
due primarily
to arteriosclerosis,
diabetes
mellitus,
or cancer
( I ). The gene has been
mapped
to chromosome
8pl 1 . 1-21 . 1 in both
Japanese
and
1-37-1,
Caucasians
(2,
3).
Since
1940,
of
unusual
Abstract
cancer
The association
between
genetic
disorders
and diverse
cancers
has provided
clues for laboratory
research
into
carcinogenesis.
Such an opportunity
now arises
from
studies
of cancer
in Werner
syndrome
(WRN).
Soft-tissue
sarcoma
(STS)
and benign
meningioma
have been
associated
with WRN,
an autosomal
recessive
disorder
characterized
by premature
aging,
more commonly
reported
in Japan
than elsewhere,
in part because
of
inbreeding.
In the literature
we found
124 case-reports
of
neoplasia
and WRN from Japan
and 34 from outside
Japan,
1939-August
1995. They reveal
a greater
diversity
of neoplasia
in WRN
than was previously
known.
In
Japanese,
there were 127 cancers,
14 benign
meningioma,
and 5 myeloid
disorders,
as compared
with 30, 7 and 2
respectively
in non-Japanese.
The ratio of epithelial
to
non-epithelial
cancers
was about
1 : 1 for Japanese
and for
non-Japanese
instead
of the usual 10:1. Both series had
excesses
of STS, osteosarcoma,
myeloid
disorders,
and
benign
meningioma.
In addition,
the Japanese
had an
excess
of thyroid
cancer
(20 versus
2 cases in nonJapanese)
and melanoma
(21 versus
3 cases),
including
5
intranasal
and 13 of the feet. STS, osteosarcoma,
melanoma,
and thyroid
carcinoma
accounted
for 57% of
all cancer
in WRN as compared
with 2% expected
based
on the Osaka
population
at 25-64
years
of age. Multiple
tumors
were reported
in 19 Japanese
and 5 nonJapanese.
In Japan,
nine first-degree
relatives
had WRN
and cancer,
six of whom
were concordant
as to site and/
or cell type. The WRN gene has been mapped
to
chromosome
8p The high frequency
of thyroid
cancer
and melanoma
in Japanese,
not found
in Caucasians,
may
be related
to a report
of linkage
disequilibrium
with the
WRN gene in Japanese
but not in Caucasians
and to
haplotype
differences
within
and between
the two races,
suggesting
multiple
independent
mutations.
recent
review
years
ago,
Japanese
case
WRN
there
reports
of
associated
been
neoplasia
in
an
was
124
revealed
by
the
Japanese
reviews
as
of
the
in WRN
has led to
(82 since
1985),
as
1985). Many of the
patients
literature
of
most
(4) 13
by Salk
partial
interest
excess
( 1 ). The
Japan
two
Japanese
6).
with
sarcomas
outside
have
(5,
in the
rest
of
of neoplasms
compared
with
case
reports
from other countries.
Similar
case series in the past have
determined
the array of cancers
in genetic
syndromes,
which
led laboratory
investigation
to the first recognition,
for exampie, of tumor suppressor
genes (7, 8), and germline
mutations
of the p53 gene (9).
Materials
and
Methods
In Japan,
the literature
has been searched
for publications
on
WRN
through
a citation
index
(Igaku-Chuo-Zasshi,
19601986) and its continuation
as a computer
index since 1987. For
cases
outside
Japan,
searches
were
made
by computer
(Medline
and Cancerlit)
since 1966. Bibliographies
of each report
1939 were
examined
for additional
references.
Care
taken
to exclude
multiple
reports
of the same
patient,
ognized
by details
of family
and personal
histories
demographic
characteristics.
Diagnosis
criteria
stocky
hair,
of
under
trunk
the
spindly
original
except
in Japanese
because
(one
uterus,
conclusions.
included
for
each
ovary,
with
one
of
its
of
stomach,
and
benign
in the totals,
occurs
only
used
for
or
given
throughout
the
and
Seven
diag-
counted
in the
cavity,
as
organs
esophagus,
pan-
a conservative
without
tumors
as
in Japanese
were
to give
cancer
4
and
mellitus
black.
“cancer”
nasal
3 of
(gray
was
predominance
brain
but are
The abbreviations
used are: WRN.
syndrome;
AML. acute myelogenous
noma; LFS, Li-Fraumeni
syndrome.
3
WRN
States
and
to epithelial
Two
(diabetes
neoplasia
as
marked
skin)
of
stature
scleroderma-
neoplasia
given
since
was
recand
senescence
of
United
were
(short
disorders
Although
that
presence
arteriosclerosis),
Diagnosis
reported
the
habitus
premature
and
authors.
it has been
carcinoma
limbs),
10).
on
body
and endocrine
Ref.
Caucasians,
noses
based
osteoporosis,
like skin changes,
world,
was
unusual
35:
with
cataracts,
hypogonadism;
by
WRN
age
of non-epithelial
Branch,
EPN-400,
National
Cancer
Institute,
Bethesda,
MD 20892-7360.
2 This
binational
collaboration
developed
from a workshop
on cancer
clusters
held by the U.S-Japan
Collaborative
Cancer
Research
Program
in March
1994.
been
especially
of the literature
and
literature
involved
of
in
has
types,
compared
with 34 outside
Japan (4 since
Japanese
case reports
are in journals
not available
the world. Reported
here is the remarkable
array
creas,
Received
10/26/95;
revised
1/8/96:
accepted
1/9/96.
The costs of publication
of this article
were defrayed
in part by the payment
page charges.
This article
must therefore
be hereby
marked
advertisement
accordance
with 18 U.S.C.
Section
1734 solely to indicate
this fact.
I To
whom
requests
for reprints
should
be addressed,
at Genetic
Epidemiology
Biomarkers
Introduction
and
Department
of Rheumatic
Diseases,
Tokyo
Metropolitan
Otsuka
Hospital.
2-8-I,
Minami-Otsuka,
Toshima-ku.
Tokyo
170, Japan
IM. 0.1: Genetic
Epidemiology
Branch.
National
Cancer
Institute,
Bethesda,
Maryland
208927360 IR. W. M.J: and Cancer
Institute,
Kami-Ikebukero,
Toshima-ku.
Tokyo
170. Japan
IY. I.. H. S.I
Syndrome
Epidemiology,
affecting
in
the
Wemer syndrome:
leukemia;
ALM.
ratio
Japanese
ratio
other
are
not
of meningioma
MDS,
acral
myelodysplastic
lentiginous
mela-
Downloaded from cebp.aacrjournals.org on November 2, 2016. © 1996 American Association for Cancer Research.
240
Rare Cancers
in Werner
Syndrome
to other
brain
tumors,
to
series.
Publishing
on cancer
elsewhere
because
of space
small, specialized,
or local
were ascertained
through
those from outside
Japan
indices
that
do
not
allow
comparison
with
published
in WRN
is easier
in Japan
than
available
in a substantial
number
of
journals.
The case reports
in Japan
a national
citation
index,
whereas
were ascertained
from international
cover
most
of
the
Japanese
reports
cited
here. The cases in Japan were thus more fully ascertained
than
were the cases outside
Japan.
The interpretation
of the data
depends
on the distribution
by cell type for each case series as
compared
with one another
and with the general
population.
Results
The 34 non-Japanese
cases of WRN with cancer occurred
in the
United
States (13 cases),
Canada
(2 cases),
Sardinia
(5 cases),
elsewhere
in western
Europe
( I 3 cases)
and Turkey
( 1 case).
Consanguineous
parentage
was reported
in 56 of 80 Japanese
cases
(70%)
for
whom
this
information
was
published,
and
in
14 of 30 cases (47%)
outside
Japan.
The 124 Japanese
cases occurred
throughout
the nation.
They had 127 cancers,
14 benign
meningiomas,
and 5 cases of
MDS
and/or
myelofibrosis.
In the series
outside
Japan
there
were 30 cancers,
7 benign
meningiomas,
and I case each of
MDS
and myelofibrosis;
19 Japanese
and 5 Caucasians
had
more than one of these diagnoses.
Thyroid
carcinoma
accounted
for 14% of neoplasia
in
Japanese
with WRN
as compared
with 3% in non-Japanese.
When
benign
meningioma
and preleukemic
disorders
were
excluded,
the ratio of epithelial
to non-epithelial
cancer was I: 1
in Japanese
and non-Japanese
(Table
1 ), as compared
with 10:1
in the general
adult population
(1 1). Soft-tissue
sarcomas,
23 in
Japan and 7 elsewhere,
were of diverse
cell types;
8 cases of
osteosarcoma
were reported
in Japan
and 4 elsewhere.
The
anatomic
site of osteosarcoma
was unusual
in three cases:
the
patella
in a Japanese
(38) and the small bones of the feet (29)
and orbit (45) in Caucasians.
Melanoma
is rare in Japanese,
but not among
those with
WRN. The distribution
by site among the 21 cases was unusual:
13 were of the feet (23, 49, 52-61 ), 5 were intranasal
(46-49),
and I was esophageal
(50).
Two Japanese
and one United
States patient had double
primary
melanoma
(Table
1 ; Refs. 49,
52, and 63).
Meningioma
was frequent
in both series:
15 cases
in
Japan,
1 of them malignant
(74), and 7 outside
Japan.
One in
each series was multiple
(45, 65); all the tumors
described
were
intracranial,
in the usual locations.
Although
meningioma
in the
general
population
is predominately
in women,
the sex ratio
(male:female)
in Japanese
with WRN
was 12:2 (1 sex unknown).
Among
the Japanese,
eight cases had leukemia,
specified
as AML
in five (84-88)
and erythroleukemia
in one (89).
Precancerous
hematological
disorders
consisted
of five with
MDS and/or myelofibrosis.
Among
Caucasians,
two cases had
leukemia
(31, 94), one had MDS (95), and one had myelofi-
brosis
(96). The sex was given
in 13 of 14 Japanese
with these
all but one were male.
The most frequent
epithelial
cancer
among
Japanese
was
thyroid
carcinoma.
Twenty
Japanese
cases were diagnosed
premortem
and 5 postmortem.
The cell type was primarily
follicular or papillary.
Only two Caucasians
had thyroid
cancer,
one
of them found at postmortem.
diagnoses,
and
Nonmelanotic
those
in Japanese
skin
cancers
7 to 3. The
Japanese
in
Caucasians
had
38 other
as compared
four biliary
patic (122),
with 5 in non-Japanese.
cancers
[two intrahepatic
and one gall bladder
extrahepatic
bile-duct
carcinoma
The
(120,
(123)]
in
most notable
were
121), one extrahein Japan,
and one
the
United
States
Discussion
In a case
syndrome
difference
and/or
series,
associations
between
specific
cancers
and a
such as WRN can be revealed
by demonstrating
a
from the usual distribution
of cancer
by cell type
site.
In
our
study,
a marked
difference
from
the
usual
distribution
was found.
The excess
of non-epithelial
cancers
was due largely
to sarcoma
in both series. The annual
incidence
of soft-tissue
sarcoma
at ages 25-64
was 0.9/100,000
in the
general
population
of Osaka (143). If one assumes
that in Japan
the 8 10 known
cases of WRN come from a total of 5000 cases
[a high estimate
based on genotype
frequency
estimates
from
segregation
analysis
(5) and three
times
the prevalence
in
inbred
populations
in Sardinia
(144)],
1 soft-tissue
sarcoma
would be expected
every 20 years, as compared
with 23 cases
observed
in Japanese
with WRN.
One can view the Japanese
data as establishing
the excess,
and
the experience
outside
Japan as confirmatory.
Osteosarcoma
(eight cases in Japan and
four elsewhere)
was also excessive,
given that its annual
mcidence in Osaka
at ages 25-64
was 0.45/l00,000
(143). Osteosarcoma,
which
normally
has
a peak
in
late
adolescence,
outnumbered
carcinomas
(77).
There
were no reports
of lymphoma
or colorectal
carcinoma,
and only one case each of pulmonary,
pancreatic,
esophageal,
and prostatic
carcinoma
(Table
1). Overall,
the Japanese
had
substantially
higher
frequencies
than non-Japanese
of thyroid
carcinoma,
melanoma,
and the category
“other
carcinoma.”
Neoplasia
was diagnosed
in WRN
between
25 and 64
years of age, except
for a Japanese
with osteosarcoma
at 20
years4 and a Canadian
with AML at 24 years (94). There were
no substantial
differences
in age distribution
according
to tumor
type. In this age range, four rare cancers
(soft-tissue
sarcoma,
osteosarcoma,
melanoma,
and
thyroid
cancer)
accounted
for
57% of all cancer
in Japanese
with WRN as compared
with 2%
in the general
population
of Osaka
(143).
Nineteen
Japanese
with WRN
and 5 non-Japanese
had
multiple
primary
neoplasms,
or neoplasia
with MDS or myelofibrosis
(Table 2). The frequency
of multiple
primary
neoplasia
was the same (15%)
in both series,
but among
the Japanese,
thyroid
carcinoma
occurred
in 10 cases (cases
1-9 and 1 1), a
neoplasm
to which
Caucasians
with WRN
were not prone.
Meningioma
occurred
in 5 Japanese
(cases 8 -1 2), one of whom
developed
MDS (67) and another
of whom
developed
myelofibrosis
(68) after removal
of the meningioma
(cases
I 1 and
12). Three Caucasians
also had meningioma
and another
neoplasm (cases
3’-S’).
In Japan, nine first-degree
relatives
with cancer
and WRN
have been reported
(Table
3), six of whom
were concordant
with the index patient
as to the site and/or
type of cancer
and
were of similar
age (families
1-6). Two sisters
had intranasal
melanoma
(46), two brothers
had fibrosarcoma
of the leg (5),
and a trio of siblings
had soft-tissue
sarcoma
at the elbow
(two
malignant
fibrous
histiocytoma
and one leiomyosarcoma;
Ref.
I 9). In only one Caucasian
sibship
were two members
affected,
with neoplasms
of discordant
type. Genotype/phenotype
correlations in the Japanese
may be due to a mutation
that induces
a
site-specific
cancer
or to host-susceptibility
factors,
either genetic or environmental.
M. Goto,
personal
case.
oc-
Epidemiology,
Cancer
Table
/
Number
neoplasms
of type-specific
and m yeloid
disorders
in WRN
Japan
Diagnosis
among
Ja panese
as compared
Refs.
with
Blomarkers
& PreventIon
non-Japanese
Outside
Japan
Refs.
Non-epithelial
Soft-tissue
sarcoma
Schwannoma,
23
malignant
Rhabdomyosarcoma
Malignant
histiocytoma
fibrous
7
3
12-14
I
15
6
16-20
Leiomyosarcoma
5
19, 21-24
Fibrosarcoma
5
5, 25, 26
1
27
Synovial
Other
sarcoma
or not specified
2
Osteosarcoma
8 +
Melanoma
28
1”
23,
P0”
5
Esophageal
I
50
I
51
Foot
Other
23. 49,
1
15 +
Multiple
(1 malignant;
Hematological
Ref.
74)
14 +
disorders
Leukemia,
Atypical
RAEBd
62
Leukemia,
acute
14, 25,
1
83
myelogenous
5
84-88
I
89
2
67,90
91, 92
Myelofibrosis
1
68
Plasmacytoma
1
93
I
87
Brain
Total
myelofibrosis
+
tumors
non-epithelial
2
63.64
PC”
45
6
4, 77-81
4
2
MDS
63
1
66-76,
(MDS?)
MDS
1
65
1
82
Erythroleukemia
43,,45b
7
I
leukemia
29.
52-61
14
probably
33-35
4
1
1
Single
30-32
46-49
13
Meningioma
3
3’
lntranasal
acral
29
3
36-42,
21’
Lip/face,
1
82
+ 2
20
+
1
31
1
94
1
95
1
96
1
99
26
Epithelial
Thyroid
carcinoma
Follicular
9 +
Papillary
8
Anaplastic
2
V’
I +
I
5, 6, 16, 2I,
22,
14, 23,
38,
37,
89,
100,
73,
87,
101,
85,
100,
103,
102,
103,
104-106
i
1
Unknown
I
Gastriccarcinoma
Hepatocellular
carcinoma
cancer.
NOS
67,
6
23,
3
5. 1 15,
110-113
1 16
2
1 18,
carcinoma
4
120-123
Breast
carcinoma
5 +
carcinoma,
Other
non-melanotic
I
5, 60,
3
carcinoma
113,
17,
124,
19,
P0”
126
2
5. 134
Pulmonary
1
135
Esophageal
I
136
Pancreatic
I
3
Uterine,
NOS
2
38,
Ovarian
2
140,
Seminoma
I
NOS
125
46,
138,
Grand
141
126
I
14
I
105
I
143
observation
(P0)
of M. Goto
thyroid
carcinoma).
b United
States
black patient
(44).
(. Two
Japanese
counted
twice for double
+ 4
39
breast
melanoma:
carcinoma);
intranasal,
patient:
ALM of thumb
and lentigo
maligna
of the pinna (63).
d RAEB,
refractory
anemia
with excess
of blasts;
NOS,
not otherwise
e Two
Japanese
had benign
brain tumors
(97, 98).
I Biopsy
a Thyroid
or surgery;
carcinoma
excludes
diagnosed
diagnoses
at autopsy:
at autopsy.
five
142
11
(osteosarcoma,
primary
127-130
139
61 + 2
total
+ I, personal
114,
133
Prostatic
Totalepithelial
“
32,
137
bladder
neck,
77
1
131-133
Urinary
cell,
1
1
3
cell
114
1 17
7
18
Laryngeal
Squamous
1
1
1 19
Nasal/nasopharyngeal
Renal
78
108
Biliary
Skin
109
l07
Other
Liver
l
PC”
Japanese,
personal
communications
age 45, and toe, age 46 (49);
right
(PC)
ankle,
from
A. Seki
age 40,
and
(meningioma)
left
sole,
and
K. Takakuwa
age 44 (52);
(follicular
and a United
States
specified.
one
Caucasian.
241
242
Rare Cancers
in Werner
Syndrome
Table
2
Multiple
primary
neoplasia
Case
or myeloid
Diagnoses
(sex,
disorders
in WRN
Ref.
age)
Japan
I
Thyroid,
follicular
(F,”
27)
+ osteosarcoma
2
Thyroid,
follicular
(M.
39)
+ malignant
3
Thyroid,
follicular
(F,
4
Thyroid,
acral
papillary”
+ gastric
5
Thyroid,
papillary
(F, 40)
+ osteosarcoma
Thyroid.
papillary
(F, 31)
+ MDS
7
Thyroid,
papillary
(M,
3
36)
8
Thyroid.
papillary
(F, 43)
9
Thyroid,
papillary
(M,
Meningioma
(M,
44)
+
Meningioma
(M,
59)
+ MDS
fibrosarcoma
12
Meningioma
(M,
34)
+
13
Schwannoma,
14
Intranasal
melanoma
15
Intranasal
melanoma
16
Melanoma,
acral,
17
Gastric
18
Seminoma
19
Uterine
(M,
45)
+ renal
+ ALM,
toe
(M,
+
+ skin,
40)
(‘
squamous
(F, age
I‘
Fibrosarcoma,
2’
Melanoma:
mediastinum
acral
(M,
lentiginous,
46)
3’
Meningioma.
multiple
4’
Meningioma
(F, 42)
+ cholangiocarcinoma
5’
Meningioma
(F,
+
W RN
and
neoplasia
51)
(M.
age
was
maligna”
or myeloid
disorders
in first-degree
Diagnoses
relatives
Relatives
Refs.
3 siblings
19
2 MFH”.
2 fibrosarcoma,
3
2 soft-tissue
4
2 intranasal
5
2 breast.
I melanoma,
6
2 gastric
+ 4 more
7
1 leukemia.
I hepatocarcinoma
8
I esophageal,
I pancreatic
Siblings
9
1 astrocytoma.
I thyroid
Brothers
87
I leiomyosarcoma
Siblings
31
leg
Brothers
5
sarcoma
Siblings
28
Sisters
46
melanoma
nodular
3 sisters
primaries
Son,
father
MZ”
twins
60
23
82,
1 16
136,
137
Japan
I malignant
‘
multiple
fibrous
in all but
fibroxanthoma,
histiocytoma;
1 of 13 cases
1 leukemia
MZ,
monozygous.
at 35-56
years.
The
exception
a 20-year-old.5
M. Goto,
type
unknown
diphenythydantoin
cell
carcinoma
bladder
(62)
67
(41)
68
(41)
46
(43)
carcinoma
13
49
(46)
left sole
(44)
52
1 13
(55)
carcinoma
126
+ nasopharyngeal
carcinoma
(age
unknown)
133
personal
case.
basal
cell
+ concurrent
carcinoma,
lentigo
+ osteosarcoma.
face
maligna,
orbital
pinna
(57)
32
(M,
56)
63
45
(42)
77
(48)
78
specified.
In Caucasians,
the commonest
types
of melanoma
are
superficial
spreading
and nodular.
These types are rare in Japanese and affected
only one person
with WRN. ALM typically
affects
the palms,
soles, and mucosa
and differs
histologically
from superficial
spreading
and nodular
melanoma
(145).
The
rate for ALM is about 0.16 cases/lOO,000
people/year
in Japanese,
as it is in all races (146).
Virtually
no cases would
be
expected
among
5000 people
with WRN over a 20-year
interval. The I 3 melanoma
on the feet and 5 in the nasal passages
of Japanese
with WRN
suggests
that melanoma
at these ana-
5
14
73
+ multiple
unknown)
‘struma
I
curred
cell
unknown)
subungual
2
MFH,
105
(F, 26)
Japan
I
(38)
Japan
Family
Outside
neck
25
after
(F, 45)
NOS
38
carcinoma,
(44)
adenocarcinoma
carcinoma
23
plantar,
(46)
+ transitional
ankle
+ melanoma,
(44)
(F, 45)
right
+ breast,
40)
16
89
37
+ thyroid,5
(60)
myelofibrosis
malignant
38
(39)
cell
+ meningioma
10
(34)
(40)
(49)
+ meningioma
46)
NOS
(34)
AML
-
+ squamous
I 1
(M,
+ uterus,
histiocytoma
+ leiomyosarcoma
+ osteosarcoma
carcinoma
(M, all at 45)
5
F, female;
M, male; NOS. not otherwise
Thyroid
carcinoma
at autopsy.
Table
+ erythroleukeniia
6
Outside
(,
33)
(35)
fibrous
tomic sites have an origin
in common,
different
from that of
superficial
spreading
and nodular
melanoma.
The same suggestion
had been made with regard
to an apparent
excess
of
mucosal
melanoma
and ALM among
blacks
(147).
Each
series
had a substantial
number
of meningioma.
These tumors,
when benign,
as in all but one of our cases, are
not recorded
in tumor registries,
so the incidence
is not known.
In large series,
up to 25% of brain tumors
have been reported
to be meningioma
(reviewed
by Willis;
Ref.
148). Among
patients
with WRN,
other brain tumors
have been reported
in
only three Japanese
(two were benign)
and one Spaniard.
Thus,
the ratio of meningioma
to other brain tumors
is much higher
than usual in WRN.
Two Japanese
with meningioma
later developed
a precursor of myelogenous
leukemia:
MDS in one, and myelofibrosis
after treatment
with diphenylhydantoin
in the other. No report
of meningioma
with myelogenous
leukemia
or its precursors
was found in the world literature.
MDS with WRN has been reported
in three other Japanese
(two later developed
myelofibrosis;
Refs. 91 and 92) and one
Turkish
patient
(95). Myelofibrosis
following
MDS,
long regarded
as an oddity,
has recently
been reported
as a distinct
clinicopathological
entity
in 17 cases (10 primary
and 7 secondary to radiochemotherapy;
Ref. 149). Myelofibrosis
without
MDS was reported
in a Japanese
(68) and a Sardinian
(96). All
of the leukemia
cases with cell type specified
were nonlymphocytic.
The cases outside
Japan strengthen
the belief that the
occurrence
of AML and its precursors
in Japanese
with WRN
did
not
occur
by
chance.
Follicular
and papillary
thyroid
carcinoma,
in excess
among
Japanese
with WRN,
have to our knowledge
not been
described
together
previously
in any other
genetic
disorder,
except
perhaps
for familial
adenomatous
polyposis
(150). Pap-
Cancer
illary carcinoma
is transmitted
as an autosomal
dominant
trait
in a few families
( 1 5 1 ). In a study of 536 autopsies
in Japan, the
prevalence
of occult thyroid
carcinoma
was about I 8%; almost
all of these
cases
were
papillary
( I 52). Only one papillary
tumor was found at autopsy
in our Japanese
series. In any event,
the 20 clinical
cases constitute
a marked
excess
of thyroid
cancer
of diverse
types in Japanese
with WRN.
The preponderance
of the follicular
type in WRN is unusual
(153).
A prominent
feature of WRN is atrophy
and wasting
of the
soft tissue and muscles
of the limbs, giving the patient a spindly
appearance
and scleroderma-like
lesions
of the hands, feet, and
face (154).
The high frequency
of soft-tissue
sarcoma
and
osteosarcoma
in a connective
tissue disorder
raises the question
of a causal relationship.
No excess
of these sarcomas
has been
reported
in other connective-tissue
disorders,
and the excess
cancer
in WRN is not limited
to these sarcomas.
Chromosomal
instability
is seen in other genetic
disorders
with high risk of cancer
(Bloom
syndrome,
Fanconi
syndrome,
and ataxia-telangiectasia).
The pattern
of aberrations
in WRN is
dissimilar:
it is called
“variegated
translocation
mosaicism”
because
the abnormalities
range from the partial
deletion
of a
single chromosome
to multiple
translocations
of several
chromosomes,
some
occurring
as clones
(reviewed
by
The array
of neoplasms
in WRN
differs
from
classic
instability
syndromes,
which are associated
mia and/or
lymphoma,
and carcinoma
of several
157).
Survivors
of atomic-bomb
exposure
have
aberrations
that
last
for
decades.
Medical
X-ray
Salk;
Ref.
those
with
sites
4).
in the
leuke(155-
exposures
increase
the risk of certain
types of cancer that overlap
those in
excess
in WRN:
at low doses, AML and thyroid
carcinoma;
at
high doses, soft-tissue
sarcoma,
osteosarcoma,
and meningioma
(reviewed
by Miller;
Ref.
158). Every
prefecture
in Japan
contributed
to the case series; there was no excess of WRN with
cancer
near Hiroshima
or Nagasaki.
High risk of cancer
after
medical
radiation
exposure
of WRN patients
is a possibility
that
we were unable
to test because
of lack of information.
In WRN, the excess
of cancer
is from 25-65
years of age.
Because
the clinical
signs of WRN
are not apparent
until the
third decade,
the occurrence
of an increase
in childhood
tumors
would
have been unrecognizable.
No suggestion
of an excess
was seen, however,
with WRN.
in the available
family
histories
of patients
In LFS, diverse
multiple
primary
cancers
may develop
(including
soft-tissue
sarcoma
and osteosarcoma).
Familial
cancer aggregation
is more common
(1 59) than in WRN, in accord
with the clinical
mode of transmission
(autosomal
dominant
in
LFS and recessive
in WRN).
The unusual
array of cancers
in
LFS is often due to a germline
mutation
of the p53 gene that
affects
cell
cycle
control
(160).
The
gene
for
WRN
appears
also
to play an important
role in oncogenesis
and programmed
cell
death.
Other
unusual
features
of WRN
include
diminished
survival of its fibroblasts
in culture
(about
20 instead
of 60 doublings
normally,
according
to Faragher
et a!.; Ref.
161), a
diminished
level of telomerase,
associated
in the general
population
with aging (162, 163), and a disequilibrium
of genetic
markers
near
the
WRN
gene
locus
in Japanese
but not in
Caucasians,
with haplotype
differences
within and between
the
two races,
suggesting
multiple
independent
mutations
(3),
which may relate to the difference
in tumor types observed.
Epstein
(1, 164) has long emphasized
that WRN does not
meet the criteria
for premature
aging
(proportional
advancement in time of all causes of death and in all morphological
and
physiological
manifestations
of aging)
but is of great value for
Biomarkers
& Prevention
243
learning
the effects
of its gene on normal
and abnormal
development.
This is especially
true of neoplasia,
which is markedly
different
from
usual
in WRN
than
in the normal
geriatric
population.
Laboratory
research
into the origins
of the diverse
neoplasms
in WRN
should
reveal
important
clues to tumorigenic mechanisms
in the general
population.
Note
Added
in Proof
A candidate
gene for the WRN
locus has
candidate
gene for the WRN locus, Science.
been identified
in press).
(C.
E. Yu
et a!.,
A
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Excess of Rare Cancers in Werner Syndrome (Adult Progeria)

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