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Xu J , Kadariya Y , Cheung M , Pei J , Talarchek J , Sementino E , Tan Y , Menges CW , Cai KQ , Litwin S , Peng H , Karar J , Rauscher FJ , Testa JR
Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma
Cancer Res. 2014 Aug 15;74(16) :4388-97
PMID: 24928783    PMCID: PMC4165574    URL: https://www.ncbi.nlm.nih.gov/pubmed/24928783
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Malignant mesotheliomas are highly aggressive tumors usually caused by exposure to asbestos. Germline-inactivating mutations of BAP1 predispose to mesothelioma and certain other cancers. However, why mesothelioma is the predominate malignancy in some BAP1 families and not others, and whether exposure to asbestos is required for development of mesothelioma in BAP1 mutation carriers are not known. To address these questions experimentally, we generated a Bap1(+/-) knockout mouse model to assess its susceptibility to mesothelioma upon chronic exposure to asbestos. Bap1(+/-) mice exhibited a significantly higher incidence of asbestos-induced mesothelioma than wild-type (WT) littermates (73% vs. 32%, respectively). Furthermore, mesotheliomas arose at an accelerated rate in Bap1(+/-) mice than in WT animals (median survival, 43 weeks vs. 55 weeks after initial exposure, respectively) and showed increased invasiveness and proliferation. No spontaneous mesotheliomas were seen in unexposed Bap1(+/-) mice followed for up to 87 weeks of age. Mesothelioma cells from Bap1(+/-) mice showed biallelic inactivation of Bap1, consistent with its proposed role as a recessive cancer susceptibility gene. Unlike in WT mice, mesotheliomas from Bap1(+/-) mice did not require homozygous loss of Cdkn2a. However, normal mesothelial cells and mesothelioma cells from Bap1(+/-) mice showed downregulation of Rb through a p16(Ink4a)-independent mechanism, suggesting that predisposition of Bap1(+/-) mice to mesothelioma may be facilitated, in part, by cooperation between Bap1 and Rb. Drawing parallels to human disease, these unbiased genetic findings indicate that BAP1 mutation carriers are predisposed to the tumorigenic effects of asbestos and suggest that high penetrance of mesothelioma requires such environmental exposure.
Xu, Jinfei Kadariya, Yuwaraj Cheung, Mitchell Pei, Jianming Talarchek, Jacqueline Sementino, Eleonora Tan, Yinfei Menges, Craig W Cai, Kathy Q Litwin, Samuel Peng, Hongzhuang Karar, Jayashree Rauscher, Frank J Testa, Joseph R eng P30 CA010815/CA/NCI NIH HHS/ R01 CA175691/CA/NCI NIH HHS/ CA175691/CA/NCI NIH HHS/ R01 CA163761/CA/NCI NIH HHS/ P30 ES013508/ES/NIEHS NIH HHS/ P30 CA006927/CA/NCI NIH HHS/ CA-06927/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Cancer Res. 2014 Aug 15;74(16):4388-97. doi: 10.1158/0008-5472.CAN-14-1328. Epub 2014 Jun 13.