title: Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma.
abstract: 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.
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Jinfei
authors.initials: J
authors.lastname: Xu
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Yuwaraj
authors.initials: Y
authors.lastname: Kadariya
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Cheung
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Jianming
authors.initials: J
authors.lastname: Pei
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Talarchek
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Sementino
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Yinfei
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Menges
authors.affiliation: Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Kathy Q
authors.initials: KQ
authors.lastname: Cai
authors.affiliation: Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Samuel
authors.initials: S
authors.lastname: Litwin
authors.affiliation: Gene Expression and Regulation, Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Hongzhuang
authors.initials: H
authors.lastname: Peng
authors.affiliation: Gene Expression and Regulation, Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Karar
authors.affiliation: Gene Expression and Regulation, Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Rauscher
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Joseph.Testa@fccc.edu.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Testa
mesh_terms: D000818:Animals; D001194:Asbestos / Q000633:toxicity*; D004195:Disease Models, Animal; D057890:Epigenomics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D008654:Mesothelioma / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D000086002:Mesothelioma, Malignant; D051379:Mice; D018345:Mice, Knockout; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism
chemical_list: C575444:BAP1 protein, mouse; D025521:Tumor Suppressor Proteins; D001194:Asbestos; D043222:Ubiquitin Thiolesterase