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Germline CDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma

Fanélie Jouenne 1, 2 Isaure Chauvot de Beauchêne 3, 4 Emeline Bollaert 5 Marie-Francoise Avril 6 Olivier Caron 7 Olivier Ingster 8 Axel Lecesne 7 Patrick Benuisiglio 7 Philippe Terrier 1 Vincent Caumette 1 Daniel Pissaloux 9 Arnaud de la Fouchardiere 9 Odile Cabaret 1 Birama N'Diaye 1 Amélie Velghe 5 Gaëlle Bougeard 10 Graham Mann 11 Serge Koscielny 12, 13 Jennifer H. Barrett 14 Mark Harland 14 Julia Newton-Bishop 14 Nelleke Gruis 15 Remco van Doorn 15 Marion Gauthier-Villars 16 Gaelle Pierron 16 Dominique Stoppa-Lyonnet 16 Isabelle Coupier 17, 18 Rosine Guimbaud 19 Capucine Delnatte 20 Jean Yves Scoazec 1 Alexander Eggermont 21 Jean Feunteun 22 Luba Tchertanov 23 Jean-Baptiste Demoulin 5 Thierry Frebourg 24, 25 Brigitte Bressac de Paillerets 1, 2
Abstract : BACKGROUND: Sarcomas are rare mesenchymal malignancies whose pathogenesis is poorly understood; both environmental and genetic risk factors could contribute to their aetiology. METHODS AND RESULTS: We performed whole-exome sequencing (WES) in a familial aggregation of three individuals affected with soft-tissue sarcoma (STS) without TP53 mutation (Li-Fraumeni-like, LFL) and found a shared pathogenic mutation in CDKN2A tumour suppressor gene. We searched for individuals with sarcoma among 474 melanoma-prone families with a CDKN2A-/+ genotype and for CDKN2A mutations in 190 TP53-negative LFL families where the index case was a sarcoma. Including the initial family, eight independent sarcoma cases carried a germline mutation in the CDKN2A/p16INK4A gene. In five out of seven formalin-fixed paraffin-embedded sarcomas, heterozygosity was lost at germline CDKN2A mutations sites demonstrating complete loss of function. As sarcomas are rare in CDKN2A/p16INK4A carriers, we searched in constitutional WES of nine carriers for potential modifying rare variants and identified three in platelet-derived growth factor receptor (PDGFRA) gene. Molecular modelling showed that two never-described variants could impact the PDGFRA extracellular domain structure. CONCLUSION: Germline mutations in CDKN2A/P16INK4A, a gene known to predispose to hereditary melanoma, pancreatic cancer and tobacco-related cancers, account also for a subset of hereditary sarcoma. In addition, we identified PDGFRA as a candidate modifier gene
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Submitted on : Monday, February 26, 2018 - 5:20:38 PM
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Fanélie Jouenne, Isaure Chauvot de Beauchêne, Emeline Bollaert, Marie-Francoise Avril, Olivier Caron, et al.. Germline CDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma. Journal of Medical Genetics, BMJ Publishing Group, 2017, 54 (9), pp.607-612. ⟨10.1136/jmedgenet-2016-104402⟩. ⟨hal-01580787⟩



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