Germline CDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma.
(2017) Journal of Medical Genetics — Vol. 54, n° 9, p. 607-612 (2017)
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- (en) 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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Jouenne, F., Chauvot de Beauchene, I., Bollaert, E., Avril, M.-F., Caron, O., Ingster, O., Lecesne, A., Benusiglio, P., Terrier, P., Caumette, V., Pissaloux, D., de la Fouchardière, A., Cabaret, O., N’Diaye, B., Velghe, A., Bougeard, G., Mann, G. J., Koscielny, S., Barrett, J. H., et al. (2017). Germline CDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma. Journal of Medical Genetics, 54(9), 607-612. https://doi.org/10.1136/jmedgenet-2016-104402 (Original work published 2017)