Germline /P16INK4A mutations contribute to genetic determinism of sarcoma.

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 tumour suppressor gene. We searched for individuals with sarcoma among 474 melanoma-prone families with a -/+ genotype and for mutations in 190 -negative LFL families where the index case was a sarcoma. Including the initial family, eight independent sarcoma cases carried a germline mutation in the /p16 gene. In five out of seven formalin-fixed paraffin-embedded sarcomas, heterozygosity was lost at germline mutations sites demonstrating complete loss of function. As sarcomas are rare in /p16 carriers, we searched in constitutional WES of nine carriers for potential modifying rare variants and identified three in platelet-derived growth factor receptor () gene. Molecular modelling showed that two never-described variants could impact the PDGFRA extracellular domain structure.

CONCLUSION

Germline mutations in /P16, 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 as a candidate modifier gene.