Abstract
<div>Abstract<p>Malignant mesotheliomas are highly aggressive tumors usually caused by exposure to asbestos. Germline-inactivating mutations of <i>BAP1</i> 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 <i>BAP1</i> mutation carriers are not known. To address these questions experimentally, we generated a <i>Bap1</i><sup>+/−</sup> knockout mouse model to assess its susceptibility to mesothelioma upon chronic exposure to asbestos. <i>Bap1</i><sup>+/−</sup> 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 <i>Bap1</i><sup>+/−</sup> 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 <i>Bap1</i><sup>+/−</sup> mice followed for up to 87 weeks of age. Mesothelioma cells from <i>Bap1</i><sup>+/−</sup> mice showed biallelic inactivation of <i>Bap1</i>, consistent with its proposed role as a recessive cancer susceptibility gene. Unlike in WT mice, mesotheliomas from <i>Bap1</i><sup>+/−</sup> mice did not require homozygous loss of <i>Cdkn2a</i>. However, normal mesothelial cells and mesothelioma cells from <i>Bap1</i><sup>+/−</sup> mice showed downregulation of Rb through a p16(Ink4a)-independent mechanism, suggesting that predisposition of <i>Bap1</i><sup>+/−</sup> 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 <i>BAP1</i> mutation carriers are predisposed to the tumorigenic effects of asbestos and suggest that high penetrance of mesothelioma requires such environmental exposure. <i>Cancer Res; 74(16); 4388–97. ©2014 AACR</i>.</p></div>
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