BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma

Journal of Translational Medicine

Research

Hakan Alakus¹  Grace Y Lin²  Shawn E Yost³  Kelly A Frazer⁴  Randall French⁵  Kristen Jepsen⁶  Brian Woo⁷  Olivier Harismendy⁸  Andrew M Lowy⁹ 

[1] Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany;Moores UCSD Cancer Center, 3855 Health Science Drive, Maildrop 0820, 92093, La Jolla, USA;Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA, USA;Department of Pathology, University of California San Diego, La Jolla, CA, USA;Division of Genome Information Sciences, Department of Pediatrics and Rady Children’s Hospital, University of California San Diego, La Jolla, CA, USA;Division of Genome Information Sciences, Department of Pediatrics and Rady Children’s Hospital, University of California San Diego, La Jolla, CA, USA;Moores UCSD Cancer Center, 3855 Health Science Drive, Maildrop 0820, 92093, La Jolla, USA;Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA;Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA, USA;Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA;Moores UCSD Cancer Center, 3855 Health Science Drive, Maildrop 0820, 92093, La Jolla, USA;Moores UCSD Cancer Center, 3855 Health Science Drive, Maildrop 0820, 92093, La Jolla, USA;Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla, CA, USA;Moores UCSD Cancer Center, 3855 Health Science Drive, Maildrop 0820, 92093, La Jolla, USA;Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA, USA;

关键词: Genomics;    Mutations;    Tumor Suppressor;    Peritoneal;    Mesothelioma;   

DOI  :  10.1186/s12967-015-0485-1

 received in 2015-01-20, accepted in 2015-04-07,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundMalignant mesothelioma (MM) arises from mesothelial cells that line the pleural, peritoneal and pericardial surfaces. The majority of MMs are pleural and have been associated with asbestos exposure. Previously, pleural MMs have been genetically characterized by the loss of BAP1 (40-60%) as well as loss of NF2 (75%) and CDKN2A (60%). The rare peritoneal form of MM occurs in ~10% cases. With only ~300 cases diagnosed in the US per year, its link to asbestos exposure is not clear and its mutational landscape unknown.MethodsWe analyzed the somatic mutational landscape of 12 peritoneal MM of epitheloid subtype using copy number analysis (N = 9), whole exome sequencing (N = 7) and targeted sequencing (N = 12).ResultsPeritoneal MM display few copy number alterations, with most samples having less than 10 Mbp total changes, mostly through deletions and no high copy number amplification. Chromosome band 3p21 encoding BAP1 is the most recurrently deleted region (5/9), while, in contrast to pleural MM, NF2 and CDKN2A are not affected. We further identified 87 non-silent mutations across 7 sequenced tumors, with a median of 8 mutated genes per tumor, resulting in a very low mutation rate (median 1.3 10−6). BAP1 was the only recurrently mutated gene (N = 3/7). In one additional case, loss of the entire chromosome 3 leaves a non-functional copy of BAP1 carrying a rare nonsense germline variant, thus suggesting a potential genetic predisposition in this patient. Finally, with targeted sequencing of BAP1 in 3 additional cases, we conclude that BAP1 is frequently altered through copy number losses (N = 3/12), mutations (N = 3/12) or both (N = 2/12) sometimes at a sub-clonal level.ConclusionOur findings suggest a major role for BAP1 in peritoneal MM susceptibility and oncogenesis and indicate important molecular differences to pleural MM as well as potential strategies for therapy and prevention.

【 授权许可】

Unknown   
© Alakus et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.