Brigitte Bressac- de Paillerets

Brigitte Bressac-de Paillerets is Molecular Geneticist at Gustave Roussy comprehensive cancer center and belongs to INSERM U1279 team for her research duties. She obtained a PharmD degree at PXI University and a PhD degree in Molecular Genetics at PV University, after 2,5 years training as a Research fellow at Harvard Medical School and Massachusetts General Hospital, Boston. After her return in France, she was hired at Gustave Roussy where she set up one of the first oncogenetics laboratory mid- 1991. Since, her main focus is translational research in oncogenetics. She conducted many bench to bedside studies, particularly in melanoma genetic epidemiology starting in 1994, through collaborations with Gustave Roussy’s Dermatologist, Pr Marie-Françoise Avril, the Epidemiologist Florence Demenais, a network of French Dermatologists and Oncogeneticists, the basic scientists Corine Bertolotto and Robert Ballotti (U1065) and the International consortium GenoMEL (https://genomel.org/). With her partners, she discovered the first oncogenic germline mutation (MITF p.E318K) affecting a sumoylation site, the one of MITF transcription factor, and increasing the risk to develop a melanoma or a kidney cancer or both, in carriers. Next, they deciphered partly the molecular mechanisms behind melanocytes transformation through loss of MITF sumoylation. Very recently, through collaboration with IARC scientists Jean Noel Hubert and Estelle Chanudet, a datamining of 46 germline WES of melanoma and kidney cancer-affected patients showed enrichment in rare germline variants in genes of the PI3K/mTOR pathway, in addition to the recurrent MITF p.E318K. She also discovered that the main melanoma predisposing gene, CDKN2A could predispose carriers to sarcomas, perhaps with a modifier gene, PDGFRA. Actually, she conducts with her students, datamining of germline WES of pediatric melanoma-affected patients and functional studies of candidate drivers, in collaboration with several teams: Arnaud de la Fouchardiere (CLB, Lyon), Mehdi Khaled (U1279), Sergey Nikolaev (U1025), Corine Bertolotto and Robert Ballotti (U1065), Valérie Castellani and Céline Delloye-Bourgeois (CNRS UMR 5310 - INSERM U1217). Patients are included thanks to a network of Dermatologists, Onoco-Pediatricians and Oncogeneticists.

Skin melanoma of the child or adolescent is very rare but its incidence increases, mainly in adolescents. The main risk factors identified are the presence of a giant congenital nevus, atypical nevus syndrome or a large number of nevi, Xeroderma Pigmentosum recessive genetic disease, immunodeficiency situations or a family history of melanoma. Surprisingly, the study of the CDKN2A gene (the main melanoma predisposing gene, causing about 30-40% of familial 3 cases- forms) in young people who developed melanoma before 18 years showed that constitutional mutations of this gene were very rare. Recent studies of somatic genetics have shown that the melanomas of the child were different from those of the adult whereas those of the adolescent were comparable.

Our project aims to study the genetic mechanisms responsible for the occurrence of pediatric melanomas, without a family history of melanoma. Our working hypothesis is that some of these melanomas occur as a result of a de novo genetic "accident" occurring either in parental gametes or post-zygotically during the development of the neural crest. In collaboration with the Evry CNG, we obtained sequencing data of constitutional exomes (on DNA extracted from the blood) of 41 trios (child and parents), 14 solos of melanoma of the child, completed by exomes of 6 Frozen tumors. Bioinformatic analyses showed the existence of early germinal or post-zygotic de novo mutations of genes involved in neural crest development or cancers, in 5 cases (4 genes). For two children whose melanoma developed on a giant congenital nevus, a post-zygotic mutation was identified on NRAS oncogene, as previously described. A 6th child carries a mutation of the gene CDKN2A, inherited from the father.

We are actually conducting functional studies on selected mutants in the HMEL line, derived from normal human melanocytes from neonatal foreskins, transduced by four sequential retroviral infections using a vector expressing hTERT, CDK4R24C, a dominant negative TP53 mutant, TP53DD and finally the BRAFV600E oncogene. We are also conducting developmental studies in the chick embryo. In parallel, we are increasing the number of samples studied through additional germline and tumoral WES.

This project will highlight the mechanisms of melanocytic oncogenesis of the child, in order to improve their diagnostic and therapeutic management.