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Kadariya Y , Cheung M , Xu J , Pei J , Sementino E , Menges CW , Cai KQ , Rauscher FJ , Klein-Szanto AJ , Testa JR
Bap1 is a bona fide tumor suppressor: genetic evidence from mouse models carrying heterozygous germline Bap1 mutations
Cancer Res. 2016 Feb 19;76(9) :2836-44
PMID: 26896281    PMCID: PMC4873414    URL: http://www.ncbi.nlm.nih.gov/pubmed/26896281
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Individuals harboring inherited heterozygous germline mutations in BAP1 are predisposed to a range of benign and malignant tumor types, including malignant mesothelioma, melanoma, and kidney carcinoma. However, evidence to support a tumor suppressive role for BAP1 in cancer remains contradictory. To test experimentally whether BAP1 behaves as a tumor suppressor, we monitored spontaneous tumor development in three different mouse models with germline heterozygous mutations in Bap1, including two models in which the knock-in mutations are identical to those reported in human BAP1 cancer syndrome families. We observed spontaneous malignant tumors in 54 of 93 Bap1-mutant mice (58%) versus 4 of 43 (9%) wild-type littermates. All three Bap1-mutant models exhibited a high incidence and similar spectrum of neoplasms, including ovarian sex cord stromal tumors, lung and mammary carcinomas, and spindle cell tumors. Notably, we also observed malignant mesotheliomas in two Bap1-mutant mice, but not in any wild-type animals. We further confirmed that the remaining wild-type Bap1 allele was lost in both spontaneous ovarian tumors and mesotheliomas, resulting in the loss of Bap1 expression. Additional studies revealed that asbestos exposure induced a highly significant increase in the incidence of aggressive mesotheliomas in the two mouse models carrying clinically relevant Bap1 mutations compared with asbestos-exposed wild-type littermates. Collectively, these findings provide genetic evidence that Bap1 is a bona fide tumor suppressor gene, and offer key insights into the contribution of carcinogen exposure to enhanced cancer susceptibility.
Kadariya, Yuwaraj Cheung, Mitchell Xu, Jinfei Pei, Jianming Sementino, Eleonora Menges, Craig W Cai, Kathy Q Rauscher, Frank J Klein-Szanto, Andres J P Testa, Joseph R Cancer Res. 2016 Feb 19. pii: canres.3371.2015.