Centre Léon Bérard Dpt of Medicine Dpt of Translational

Centre Léon Bérard Dpt of Medicine Dpt of Translational

Pierre Saintigny
Centre Léon Bérard
Dpt of Medicine
Dpt of Translational Research &
Innovation
Cancer Research Center of Lyon
Dpt of Cancer Cell Plasticity
Team EMT and Cancer Cell
Plasticity (A. Puisieux)
(I)HNPACT: Une approche intégrée de la prévention
WP1-Translationel
Investigateur Principal
P Saintigny
Co-investigateurs
P Zrounba, P Breton, A Gleizal, G Bettega, T Alix, AG Bodard
WP2-Recherche fondamentale
Investigateur Principal
P Saintigny
Co-investigateur
O Damour
WP3-Sociologie et addictologie
Investigateur Principal
V Régnier
Co-investigateur
F Chauvin, P Arvers, C Lasset
WP4-Médico-économique
Investigateur Principal
L Perrier
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Oral leukoplakia
A model of oral tumorigenesis
PHASE REVERSIBLE
PHASE IRREVERSIBLE
0 à 30 ans
normal
Invasive
Illustrations: Service chirurgie maxillo-faciale, Pitié Salpêtrière
http://www.intechopen.com ; Modern Pathology 2012
Muqueuse
normale
9p
Hyperplasie
LOH
3p, 17p
Dysplasie
11q,13q,
14q
Carcinome
in situ
6p, 8,
4q
Carcinome
invasif
« Vogelgram » proposé par Califano et al, 1996
Jean-Philippe Foy, Chloé Bertolus, Pierre Saintigny
Value of LOH
for oral cancer risk assessment
Systematic review and meta-analysis
Collaboration:
-Scott M Lippman, William WN Jr. (EPOC, USA)
-Miriam Rosin (Canada)
Halter L…Pérol D, Saintigny P, in preparation
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Background
• Oral leukoplakia is the most frequent potentially
malignant oral lesion
• Our ability to predict oral cancer (OC) risk remains poor
• DNA methyltransferase-3B (DNMT3B) gene expression
is a strong predictor of OC development
• CpG Island Methylation Phenotype (CIMP) may occur
early during OC development
Foy JP…Saintigny P. Cancer Prev Res (Phila) 2015;8(11):1027-35.
DNMT3B, a de novo methyltransferase,
is a predictor of OC development
Identification of new DNA methylation
markers of oral cancer risk
Method
Material
Patient selection & design Methylated CpG island AMplification
CpG Island Methylator Phenotype is an
early event in oral tumorigenesis
CIMP in oral preneoplasia
Selection of candidate genes
Foy JP…Saintigny P. Cancer Prev Res (Phila) 2015;8(11):1027-35.
Promoter methylation of candidate
genes in cancer (2 independent studies)
Promoter methylation of 32/86 candidate
genes in 10 OC and matched nal mucosa &
blood (DREAM)
Average β-values of 62/86 candidate
genes (125 probes) in HNSCC, blood &
nal mucosa (GSE25083)
N=91
N=146
N=18
Foy JP…Saintigny P. Cancer Prev Res (Phila) 2015;8(11):1027-35.
Downregulation of candidate genes in
tongue cancer compared to normal tongue
A gene expression index was computed in 20 matched OSCC and
normal oral mucosa by averaging the log2 expression values of 42/86
candidate genes (62 probesets, HG-U95av2, GSE13601)
Foy JP…Saintigny P. Cancer Prev Res (Phila) 2015;8(11):1027-35.
AGTR1, FOXI2, HOXA9, PENK &
LINE1 are often methylated in HNSCC
Promoter methylation (average β-values) of AGTR1, FOXI2, HOXA9, PENK, and ZIC1
in HNSCC, nal mucosa, and blood (GSE25083)
Data from Poage GM et al. Clin. Cancer Res. 2011
(GSE25093, Illumina HumanMethylation27)
Foy JP…Saintigny P. Cancer Prev Res (Phila) 2015;8(11):1027-35.
AGTR1, FOXI2, PENK and LINE1
methylation* in 37 oral leukoplakia
not included in the training set
* By pyrosequencing
Group A: 23 patients with oral leukoplakia who did not develop OC
Group B: 14 patients with oral leukoplakia who developed OC
Foy JP…Saintigny P. Cancer Prev Res (Phila) 2015;8(11):1027-35.
Methylation index, LINE1 methylation
and oral cancer-free survival
Methylation index and
OCFS
100
% survival
% survival
100
75
50
25
LINE1 methylation and
OCFS
MI LOW
MI HIGH
0
0 2 4 6 8 10 12
OCFS (years)
OCFS: oral cancer-free survival
Methylation index (MI): average % of AGTR1, FOXI2, and PENK
promoter methylation
75
50
25
LINE1 LOW
LINE1 HIGH
0
0 2 4 6 8 10 12
OCFS (years)
Foy JP…Saintigny P. Cancer Prev Res (Phila) 2015;8(11):1027-35.
Methylation index, LINE1 methylation
and DNMT3B gene expression
Methylation index and
DNMT3B
Methylation index (MI): average % of AGTR1, FOXI2, and PENK
promoter methylation
LINE1 methylation and
DNMT3B
Foy JP…Saintigny P. Cancer Prev Res (Phila) 2015;8(11):1027-35.
Conclusion
• AGTR1, FOXI2 and PENK promoter methylation
may be associated with an increased OC risk in
patients with oral leukoplakia
• Methylation index correlates with DNMT3B
expression
• Global DNA hypomethylation (LINE1) is an early
event in OC development
Foy JP…Saintigny P. Cancer Prev Res (Phila) 2015;8(11):1027-35.
Remerciements
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Collaborateurs IHNPACT-RA
T
Alix
Centre Léon Bérard
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Marie-Alexandra Albaret
Geneviève De Souza
Solène Marteau
Jean-Philippe Foy
Arnaud Paré
Sophie Deneuve
Sylvie Lantuejoul
Carole Crozes
Isabelle Treilleux
Sandra Ortiz-Cuaran
Aurélie Swalduz
Andy Karabajakian
David Pérol
Christine Lasset & Dominique
Triviaux
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Autres collaborateurs IHNPACT
– Chloé Bertolus (Pitié-Salpétrière)
– Dominique Goga, Gonzague De
Pinieux (Tours)
– Jean Perriot, Georges Brousse,
Frédérique Penault-Llorca
(Clermont-Ferrand)
– Anne Stoebner (Montpellier)
– Nathalie Wirth (Nancy)
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Collaborateurs US/Canada
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Scott Lippman, San Diego
Li Mao, Baltimore
Mark Lingen, Chicago
Waun Ki Hong, J. Jack Lee, William,
WN Jr., Houston
– Miriam Rosin, Canada
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Financeur
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