Germline Mutation of Bap1 Accelerates Development of Asbestos-Induced Malignant Mesothelioma

Abstract

Malignant mesotheliomas are highly aggressive tumors usually caused by exposure to asbestos. Germlineinactivating 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 þ/À knockout mouse model to assess its susceptibility to mesothelioma upon chronic exposure to asbestos. Bap1 þ/À 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 þ/À mice than in WT animals (median survival, 43 weeks vs. 55weeks after initial exposure, respectively) and showed increased invasiveness and proliferation. No spontaneous mesotheliomas were seen in unexposed Bap1 þ/À mice followed for up to 87 weeks of age. Mesothelioma cells from Bap1 þ/À mice showed biallelic inactivation of Bap1, consistent with its proposed role as a recessive cancer susceptibility gene. Unlike in WT mice, mesotheliomas from Bap1 þ/À mice did not require homozygous loss of Cdkn2a. However, normal mesothelial cells and mesothelioma cells from Bap1 þ/À mice showed downregulation of Rb through a p16(Ink4a)-independent mechanism, suggesting that predisposition of Bap1 þ/À 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. Cancer Res; 74(16); 4388-97. Ó2014 AACR.

BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations

“…A recent study in mice showed that the heterozygous deletion of BAP1 increased the susceptibility to mesothelioma induced by chronic exposure to asbestos; interestingly, transformed mesothelial cells acquired a second hit and showed biallelic loss of BAP1 gene. 75 BAP1 haploinsufficiency, however, is not sufficient to promote spontaneous tumorigenesis in the host, as no mesotheliomas or other malignancies were observed in unexposed mice during 87 weeks of surveillance.…”

BAP1, a tumor suppressor gene driving malignant mesothelioma

“…Utilizing zinc-finger mediated genomic DNA modifications, we created three Bap1 mouse models (49,50). In the first study (50), a heterozygous Bap1-null model in the FVB mouse strain was created by introducing a deletion of exons 6 and 7.…”

“…Similar to a previous study (51), homozygous mice were found to be embryonic lethal, indicating an essential embryonic function for the gene. More importantly, was the discovery that heterozygous Bap1 knock out (KO) mice were more susceptible to MM development after peritoneal injection of crocidolite asbestos (50). Compared to wild type (WT) littermates, there was a greater than 2-fold increased incidence of MM tumors in Bap1 KO mice (32% versus 72%, P<0.01) as well as an overall decrease in survival after asbestos exposure (55 versus 43 weeks median, P<0.0001).…”

Asbestos-Induced Mesothelial to Fibroblastic Transition Is Modulated by the Inflammasome

“…injection model of asbestos exposure developed by Goodlick et al 16 and recently used by various groups. 17,18 All these studies revealed the development of early inflammation, 17 peritoneal fibrosis, and eventually MM in mice 16,18 in response to asbestos. Inhalation or aspiration models were not considered for this study because asbestos exposure by either model did not cause peritoneal fibrosis or MM in mice.…”