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.
- Genetic epidemiology
- Molecular genetics
- Connective tissue disease
- Cancer: dermatological
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Contributors BB-deP, J-BD, LT and TF designed the study; TF, OC, OI, M-FA, AL, PB, PT, DP, AdlaF, OC, IC, GJM, MH, JN-B, NG, RVD, RG, CD, MG-V, GP and DS-L provided patients clinical data and samples. FJ, EB, VC, IC-de B, GB and AV performed the experiments. FJ, IC-deB, BND, BB-deP, J-BD, LT, JB and SK were involved with data analyses and interpretation. FJ, BB-deP, JF, LT, JB-D, AE, PB, M-FA, TF and J-YS wrote and reviewed the manuscript.
Funding This work was supported by an INCA grant 2013-1-MELA-05 and personal donations from C. and N. de Paillerets and M-H. Wagner, awarded to B.B.- d.P. The work of R.v.D and N.A.G. was supported by the Dutch Cancer Society (UL 2012-5489) and grant # R01 CA83115 from the National Cancer Institute to GenoMEL international consortium.
Competing interests None declared.
Patient consent All patients signed informed consent for research genetic analysis, approved by the concerned IRBs.
Ethics approval CPP Nord Ouest N2015/160/HP; CPP Ile de France 2, IRB#00001072, N2010-01-09.
Provenance and peer review Not commissioned; externally peer reviewed.