Germline CDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma - Inria - Institut national de recherche en sciences et technologies du numérique Access content directly
Journal Articles Journal of Medical Genetics Year : 2017

Germline CDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma

Marie-Francoise Avril
  • Function : Author
  • PersonId : 907532
Olivier Ingster
  • Function : Author
  • PersonId : 918890
Daniel Pissaloux
  • Function : Author
  • PersonId : 768539
  • IdRef : 17847147X
Marion Gauthier-Villars
  • Function : Author
  • PersonId : 907333
Capucine Delnatte
  • Function : Author
  • PersonId : 910040
Alexander Eggermont
  • Function : Author
  • PersonId : 942521
Jean Feunteun
  • Function : Author
  • PersonId : 907567


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
Fichier principal
Vignette du fichier
jouenne_2017.pdf (718.2 Ko) Télécharger le fichier
Origin : Files produced by the author(s)

Dates and versions

hal-01580787 , version 1 (26-02-2018)



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, 2017, 54 (9), pp.607-612. ⟨10.1136/jmedgenet-2016-104402⟩. ⟨hal-01580787⟩
748 View
593 Download



Gmail Facebook X LinkedIn More