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BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma
BACKGROUND: Malignant 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%)...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422481/ https://www.ncbi.nlm.nih.gov/pubmed/25889843 http://dx.doi.org/10.1186/s12967-015-0485-1 |
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author | Alakus, Hakan Yost, Shawn E Woo, Brian French, Randall Lin, Grace Y Jepsen, Kristen Frazer, Kelly A Lowy, Andrew M Harismendy, Olivier |
author_facet | Alakus, Hakan Yost, Shawn E Woo, Brian French, Randall Lin, Grace Y Jepsen, Kristen Frazer, Kelly A Lowy, Andrew M Harismendy, Olivier |
author_sort | Alakus, Hakan |
collection | PubMed |
description | BACKGROUND: Malignant 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. METHODS: We 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). RESULTS: Peritoneal 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. CONCLUSION: Our 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12967-015-0485-1) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4422481 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-44224812015-05-07 BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma Alakus, Hakan Yost, Shawn E Woo, Brian French, Randall Lin, Grace Y Jepsen, Kristen Frazer, Kelly A Lowy, Andrew M Harismendy, Olivier J Transl Med Research BACKGROUND: Malignant 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. METHODS: We 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). RESULTS: Peritoneal 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. CONCLUSION: Our 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12967-015-0485-1) contains supplementary material, which is available to authorized users. BioMed Central 2015-04-16 /pmc/articles/PMC4422481/ /pubmed/25889843 http://dx.doi.org/10.1186/s12967-015-0485-1 Text en © 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. |
spellingShingle | Research Alakus, Hakan Yost, Shawn E Woo, Brian French, Randall Lin, Grace Y Jepsen, Kristen Frazer, Kelly A Lowy, Andrew M Harismendy, Olivier BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma |
title | BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma |
title_full | BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma |
title_fullStr | BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma |
title_full_unstemmed | BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma |
title_short | BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma |
title_sort | bap1 mutation is a frequent somatic event in peritoneal malignant mesothelioma |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422481/ https://www.ncbi.nlm.nih.gov/pubmed/25889843 http://dx.doi.org/10.1186/s12967-015-0485-1 |
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