Abstract 2752: Prevalence of BAP1 germline mutations in asbestos-exposed malignant mesothelioma cases and controls

Abstract

Abstract Malignant mesothelioma (MM) is an uncommon but aggressive cancer that has been linked with asbestos exposure. Contributing genetic factors appear to play a role because familial clustering of MM has been observed and that only a small percentage of asbestos-exposed individuals have been documented to develop MM. Germline mutation of BAP1 has been identified as one such predisposing factor. However, the frequency of germline BAP1 mutations in MM cases is debatable due to small sampling sizes of studies from previous publications. Therefore, we decided to determine the prevalence of germline BAP1 mutations in a large set of asbestos-exposed MM cases and controls, the biggest such population study to date. BAP1 mutation status was compared between 150 MM cases with a family history of cancer and 153 asbestos-exposed controls without indications of familial cancers. Although no alterations of BAP1 were discovered in the controls, BAP1 mutations were identified in 9 of the MM cases (6%). These alterations included 2 splice site changes, 4 insertion/deletions, and 3 missense mutations. In vitro enzymatic assays showed decreased deubiquitinase activity for each of the three BAP1 missense mutant proteins. We observed a statistically significant lower age of MM onset as well as a higher incidence of peritoneal MMs among the 9 BAP1 mutation cases compared to the non-mutated MM cases. The other tumors identified in family members of the 9 individuals included additional MMs, ocular and cutaneous melanomas, renal, breast, lung, and gastric carcinomas, and lymphomas. Interestingly, six of the nine MM cases with a germline BAP1 mutation had two or more primary cancers, suggesting a widespread targeting of tissues of multiple organs caused by the mutation. In summary, these findings suggest that patients presenting with MM and a family history of cancer should be considered for BAP1 mutation testing to identify those who might benefit from screening and regular monitoring of family members to enable early detection and intervention. Citation Format: Mitchell Cheung, Jacqueline Talarchek, Suzanne E. Howard, Timothy Howard, Hongzhuang Peng, Mary Hesdorffer, Frank J. Rauscher, Jill A. Ohar, Joseph Testa. Prevalence of BAP1 germline mutations in asbestos-exposed malignant mesothelioma cases and controls. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2752. doi:10.1158/1538-7445.AM2015-2752