INSERM – UNIVERSITE D’EVRY
Tour Evry 2 – Génopole“
523 Place des Terrasses de l’Agora
INSTITUT GUSTAVE ROUSSY
39 rue Camille Desmoulins
EMI-0006 – INSERM–UNIVERSITE D’EVRY (Genetic Epidemiology)
Tour Evry 2
523 Place des Terrasses de l’Agora
Department of Dermatology (dermatology clinic)
Department of Genetics (molecular genetics)
Department of Medicine (oncogenetics)
Institut Gustave Roussy
39 rue Camille Desmoulins
The name, address and contact e-mail, tel of the group leader
Dr. Florence Demenais, MD
EMI-0006 – INSERM – UNIVERSITE D’EVRY
Tour Evry 2 – 523 Place des Terrasses de l’Agora
Our melanoma research program is a multidisciplinary program involving clinicians, molecular biologists and onco-geneticists from Institut Gustave Roussy and genetic epidemiologists from INSERM-Université d’Evry, working with a network of Dermatologists and Oncogeneticists.
The overall objective of our research program is to identify inherited genes and gene-environment interactions involved in melanoma pathogenesis. Large collections of data have been established over the past 15 years including families ascertained through one melanoma proband, families with at least two melanoma cases and more recently sporadic cases with multiple primary melanomas and/or young age at onset suggesting genetic predisposition. The main outcomes of this program are summarized as follows.
The rate of CKDN2A mutations identified in melanoma-prone families is one of the highest rates reported worldwide in clinically-selected families. One of these mutations (G101W) demonstrated a founder effect common to French, Italian, Spanish and North-American pedigrees and was also found in sporadic cases indicating a highly variable expression of this mutation. More recently, a CDKN2A mutation (Gly67Ser) was found to co-segregate with both cutaneous and uveal melanoma in one pedigree showing that CDKN2A is also an uveal melanoma predisposing gene. In the search for new melanoma predisposing genes, the BRAF gene, for which a high frequency of somatic mutations was reported in melanoma cell lines, primary tumors and nevi, did not appear to predispose to melanoma in our population.
Segregation analysis, based on methodology developed by our group, showed significant evidence for a major gene segregating in families ascertained systematically through one melanoma proband; interestingly the penetrance of this gene (reaching 49% in males and 67% in females by age 80 years) was similar to that of CDKN2A gene estimated in the European families of the International Melanoma Consortium. Moreover, the same factors increased the penetrance of this gene and that of CDKN2A in our French family samples: nevus phenotypes (high number of nevi, dysplastic nevi) and sunburns with a marginal effect of high degree of sun exposure. More recently, variants of MC1R gene, known to be involved in human pigmentation, were found to increase CDKN2A penetrance in addition to dysplastic nevi and sunburns in French melanoma-prone pedigrees. In addition, significant evidence for familial aggregation of melanoma risk factors was found in our series of families with at least two melanoma cases, these patterns of familial clustering being compatible with the influence of genetic factors for phototype and high number of nevi and shared environment for sun exposure.
The future aims of our research program include the search for high-risk genes in CDKN2A negative melanoma-prone families, the identification of genetic variants in candidate genes accounting for cases with low familial clustering and multiple sporadic melanoma and the characterization of gene-gene as well gene-environment interactions. A genetic study of the high number of nevi has also been undertaken that will include a genome-wide scan to characterize the chromosomal regions of interest to be further explored towards gene identification.
Our group is also involved in other research projects including clinical research on melanoma (Institut Gustave Roussy), molecular genetic studies of other cancers (Institut Gustave Roussy), as well as development of methodology in statistical genetics and genetic epidemiology of other multifactorial diseases (EMI-0006).
Institut Gustave Roussy (IGR)
Institut National de la Santé et de la Recherche Médicale (INSERM)
The names and e-mail addresses of group members with a description of their contribution
Florence Demenais, MD
Brigitte Bressac-de Paillerets, PharmD, PhD
Marie-Françoise Avril, MD
Valérie Chaudru, PhD
Data collection and management
Avril MF., Aamdal S., Grob JJ., Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saiag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y.
Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study.
J Clin Oncol, 22:1118-25, 2004.
Chaudru V., Chompret A., Bressac-de Paillerets B., the French Familial Melanoma Study Group, Avril M-F., Demenais F.
Influence of genes, nevi and sun-sensitivity on melanoma risk in a family sample unselected by family history and in melanoma-prone families.
J Natl Cancer Inst, 96: 785-795, 2004.
Ibrahim el C, Aractingi S, Allory Y, Borrini F, Dupuy A, Duvillard P, Carosella ED, Avril MF, Paul P.
Analysis of HLA antigen expression in benign and malignant melanocytic lesions reveals that upregulation of HLA-G expression correlates with malignant transformation, high inflammatory infiltration and HLA-A1 genotype.
Int J Cancer,108:243-50, 2004.
Kannengiesser C., Avril M-F., Spatz A., Laud K., Lenoir G.M., Bressac-de Paillerets B.
CDKN2A as a uveal and cutaneous melanoma susceptibility gene.
Genes Chromosomes Cancer, 2003, 38: 265-268.
Gillanders,E.; Hank Juo,S.H.; Holland,E.A.; Jones,M.; Nancarrow,D.; Freas-Lutz,D.; Sood,R.; Park,N.; Faruque,M.; Markey,C.; Kefford,R.F.; Palmer,J.; Bergman,W.; Bishop,D.T.; Tucker,M.A.; Bressac-de Paillerets,B.; Hansson,J.; Stark,M.; Gruis,N.; Bishop,J.N.; Goldstein,A.M.; Bailey-Wilson,J.E.; Mann,G.J.; Hayward,N.; Trent,J.
Localization of a novel melanoma susceptibility locus to 1p22.
Am J Hum Genet, 2003, 73: 301-313.
Laud K., Kannengiesser C., Avril M-F., Chompret A., Stoppa-Lyonnet D., Desjardins L., Eychene A., Demenais F., French Hereditary Melanoma Study Group, Lenoir, G.M., Bressac-de Paillerets B.
BRAF as a melanoma susceptibility candidate gene?
Cancer Res, 2003, 63:3061-5
Fung D.C.Y., Holland E.A., Hayward N.K., Bressac-de Paillerets B., Melanoma Genetics Consortium, Mann G.J.
eMelanoBase: an online locus-specific variant database for familial melanoma.
Hum Mut, 2003, 21:2-7.
Yakobson E, Eisenberg S, Isacson R, Halle D, Levy-Lahad E, Catane R, Safro M, Sobolev V, Huot T, Peters G, Ruiz A, Malvehy J, Puig S, Chompret A, Avril MF, Shafir R, Peretz H, Bressac-de Paillerets B.
A single Mediterranean, possibly Jewish, origin for the Val59Gly CDKN2A mutation in four melanoma-prone families.
Eur J Hum Genet,11:288-96, 2003.
Kefford R., Newton-Bishop J., Tucker M., Bressac-de Paillerets B., Bianchi-Scarra G., Bergman W., Goldstein A., Puig S., Mackie R., Elder D., Hansson J., Hayward N., Hogg D., Olsson H. for the Melanoma Genetics Consortium.
Genetic testing for melanoma.
Lancet Oncology, 3: 653-654, 2002.
Bishop D.T.*, Demenais F.*, Goldstein A.M.* (*These authors contributed equally to this work), Bergman W., Newton Bishop J, Bressac-de Paillerets B., Chompret, A., Ghiorzo P., Gruis N., Hansson J., Harland M., Hayward N., Holland E.A., Mann G.J., Mantelli M., Nancarrow D., Platz A., Tucker M.A., The Melanoma Genetics Consortium.
Geographical variation in the penetrance of CDKN2A mutations for melanoma.
J Natl Cancer Inst, 94, 894-903, 2002.
Bressac-de Paillerets B., Avril M-F., Chompret A., Demenais F.
Genetic and environmental factors in cutaneous malignant melanoma.
Biochimie, 84, 67-74, 2002.
Briollais L, Demenais F.
Regressive threshold model for familial analysis of complex diseases with variable age of onset.
Avril MF, Chompret A, Verne-Fourment L, Terrier-Lacombe MJ, Spatz A, Fizazi K, Bressac-de Paillerets B, Demenais F, Theodore C.
Association between germ cell tumours, large numbers of naevi, atypical naevi and melanoma.
Melanoma Res,11:117-22, 2001.
Auroy S., Avril M-F., Chompret A., Pham D., Goldstein A.M., Bianchi-Scarrà G., Frébourg T., Joly P., Spatz A., Rubino C., Demenais F., French Hereditary Melanoma Study Group and Bressac-de Paillerets B.
Sporadic multiple primary melanoma cases : CDKN2A germline mutations with a founder effect.
Genes Chromosomes Cancer, 32: 195-202, 2001.
Briollais L., Chompret A., Guilloud-Bataille M., Bressac-de Paillerets B., Avril M-F., Demenais F.
Patterns of familial aggregation of three melanoma risk factors: great number of naevi, light phototype and high degree of sun exposure.
Int J Epidemiol., 29:408-15, 2000.
Ciotti P., Struewing J-P., Mantelli M., Chompret A., Avril M-F., Santi P.L., Tucker P., *Bianchi-Scarra G., *Bressac-de Paillerets B., and *Goldstein A.M. *These authors contributed equally to this work.
A single genetic origin for the G101W mutation in 20 melanoma-prone families.
Am J Hum Genet, 67:311-319, 2000.
Goldstein AM, Martinez M, Tucker MA, Demenais F.
Gene-covariate interaction between dysplastic nevi and the CDKN2A gene in American melanoma-prone families.
Cancer Epidemiol Biomarkers Prev, 9:889-94, 2000.