Germline <i>CDKN2A</i>/P16INK4A mutations contribute to genetic determinism of sarcoma.

Abstract

Sarcomas are rare mesenchymal malignancies whose pathogenesis is poorly understood; both environmental and genetic risk factors could contribute to their aetiology. 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 <i>CDKN2A</i> tumour suppressor gene. We searched for individuals with sarcoma among 474 melanoma-prone families with a <i>CDKN2A</i>-/+ genotype and for <i>CDKN2A</i> mutations in 190 <i>TP53</i>-negative LFL families where the index case was a sarcoma. Including the initial family, eight independent sarcoma cases carried a germline mutation in the <i>CDKN2A</i>/p16^INK4A gene. In five out of seven formalin-fixed paraffin-embedded sarcomas, heterozygosity was lost at germline <i>CDKN2A</i> mutations sites demonstrating complete loss of function. As sarcomas are rare in <i>CDKN2A</i>/p16^INK4A carriers, we searched in constitutional WES of nine carriers for potential modifying rare variants and identified three in platelet-derived growth factor receptor (<i>PDGFRA</i>) gene. Molecular modelling showed that two never-described variants could impact the PDGFRA extracellular domain structure. Germline mutations in <i>CDKN2A</i>/P16^INK4A, 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 <i>PDGFRA</i> as a candidate modifier gene.