Jouenne, F, Chauvot de Beauchene, I, Bollaert, E et al. (33 more authors) (2017) Germline CDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma. Journal of Medical Genetics, 54 (9). pp. 607-612. ISSN 0022-2593
Abstract
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 formalinfixed 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017, Article author(s) (or their employer(s) unless otherwise stated in the text of the article). All rights reserved. No commercial use is permitted unless otherwise expressly granted. This is an author produced version of a paper published in Journal of Medical Genetics. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Epidemiology and Biostatistics (Leeds) |
Funding Information: | Funder Grant number National Institute of Health - NIH (PHS) 10-17751-99-01-G5 |
Depositing User: | Symplectic Publications |
Date Deposited: | 27 Apr 2017 14:05 |
Last Modified: | 17 Jan 2018 18:41 |
Status: | Published |
Publisher: | BMJ Publishing Group |
Identification Number: | 10.1136/jmedgenet-2016-104402 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:115743 |