title: Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations.
abstract: 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. Cancer Res; 76(9); 2836-44. ©2016 AACR.
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: Jinfei
authors.initials: J
authors.lastname: Xu
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: Eleonora
authors.initials: E
authors.lastname: Sementino
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Menges
authors.affiliation: Histopathology Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Kathy Q
authors.initials: KQ
authors.lastname: Cai
authors.affiliation: Gene Expression and Regulation Program, 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. Histopathology Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Klein-Szanto
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; D055028:Comparative Genomic Hybridization; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D018095:Germ-Line Mutation; D006579:Heterozygote; D007150:Immunohistochemistry; D061346:Laser Capture Microdissection; D051379:Mice; D018345:Mice, Knockout; D009386:Neoplastic Syndromes, Hereditary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
chemical_list: C575444:BAP1 protein, mouse; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase