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Ohar JA , Cheung M , Talarchek J , Howard SE , Howard TD , Hesdorffer M , Peng H , Rauscher FJ , Testa JR
Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer
Cancer Res. 2016 Jan 15;76(2) :206-15
PMID: 26719535    PMCID: PMC4715907   
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Abstract
Heritable mutations in the BAP1 tumor suppressor gene predispose individuals to mesothelioma and other cancers. However, a large-scale assessment of germline BAP1 mutation incidence and associated clinical features in mesothelioma patients with a family history of cancer has not been reported. Therefore, we examined the germline BAP1 mutation status of 150 mesothelioma patients with a family history of cancer, 50 asbestos-exposed control individuals with a family history of cancers other than mesothelioma, and 153 asbestos-exposed individuals without familial cancer. No BAP1 alterations were found in control cohorts, but were identified in nine of 150 mesothelioma cases (6%) with a family history of cancer. Alterations among these cases were characterized by both missense and frameshift mutations, and enzymatic activity of BAP1 missense mutants was decreased compared with wild-type BAP1. Furthermore, BAP1 mutation carriers developed mesothelioma at an earlier age that was more often peritoneal than pleural (five of nine) and exhibited improved long-term survival compared to mesothelioma patients without BAP1 mutations. Moreover, many tumors harboring BAP1 germline mutations were associated with BAP1 syndrome, including mesothelioma and ocular/cutaneous melanomas, as well as renal, breast, lung, gastric, and basal cell carcinomas. Collectively, these findings suggest that mesothelioma patients presenting with a family history of cancer should be considered for BAP1 genetic testing to identify those individuals who might benefit from further screening and routine monitoring for the purpose of early detection and intervention.
Notes
Ohar, Jill A Cheung, Mitchell Talarchek, Jacqueline Howard, Suzanne E Howard, Timothy D Hesdorffer, Mary Peng, Hongzhuang Rauscher, Frank J Testa, Joseph R CA-06927/CA/NCI NIH HHS/United States CA175691/CA/NCI NIH HHS/United States P30 CA006927/CA/NCI NIH HHS/United States P42 ES023720/ES/NIEHS NIH HHS/United States R01 CA175691/CA/NCI NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States Cancer Res. 2016 Jan 15;76(2):206-15. doi: 10.1158/0008-5472.CAN-15-0295. Epub 2015 Dec 30.