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Contribition to decipher cancer heredity

Cutaneous melanoma of the child or adolescent is rare, but its incidence increases. The main risk factors identified are the presence of a congenital melanocytic nevus, an atypical nevus syndrome or a large number of nevi, recessive genetic disease such as Xeroderma Pigmentosum, immunodeficiency conditions or a family history of melanoma. Surprisingly, the study of the CDKN2A gene (main predisposition gene to melanoma, the source of 30-40% of familial > 3 melanoma cases) in young people who have developed melanoma before age 18 showed that constitutional mutations in this gene were very rare. Recent studies of somatic genetic characteristics of melanomas showed that melanoma child were different from those of adults while those of the young were comparable.
Our project aims to understand the genetic mechanisms responsible for the occurrence of pediatric melanomas without family history of melanoma. Our working hypothesis is that some of these melanomas occur following a de novo genetic "accident" occurring either in a parental gamete or post-zygotic during development of the neural crest. As part of collaboration with the CNG Evry, we obtained constitutional exomes sequencing data on 41 child-parents trios and 14 solos child melanoma cases. Bioinformatic analysis showed the existence of de novo early post-zygotic mutations of genes involved in the development of the neural crest or cancer, in 3 cases only. A 4th child carries a mutation in the CDKN2A gene, inherited from the father.
Following on from these preliminary results, our project is ongoing on two areas : (1) functional studies of these three mutations introduced into ES cells and in an experimental model of chicken embryos targeting selectively the neural crest cells ; our aim is to analyze the consequences, qualitatively and quantitatively, on differentiation and tumorigenesis of melanoblasts lineage ; (2) Due to the scarcity of potentially explained cases (4 of 41 trios), to search for late post-zygotic mutations, new exomes sequencing of constitutional and tumor at 100X depth is underway for 5 trios and one solo. Four children died of their tumor, 2 are healed.
This project should help discovering oncogenic mechanisms underlying melanoma occurrence in children. As for the discovery of the oncogene BRAF in adult melanomas, this information’s may provide new therapeutic approaches.
This project involves actually 5 partner’s teams :
(1) Dr Brigitte Bressac- de Paillerets, Dr Daniel Gautheret, Pr Caroline Robert and Pr Lex Eggermont, Gustave Roussy, Villejuif
(2) Pr Marie-Françoise Avril, Hôpital Tarnier- Cochin, Paris
(3) Dr Corine Bertolotto and Robert Ballotti, INSERM U1065, Nice
(4) Dr Sophie Creuzet, CNRS - UPR3294, Gif sur Yvette
(5) Dr Arnaud de la Fouchardière, Centre Léon Bérard, Lyon