Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations
| Autor: | Craig W. Menges, Mitchell Cheung, Kathy Q. Cai, Andres J. Klein-Szanto, Eleonora Sementino, Frank J. Rauscher, Yuwaraj Kadariya, Jinfei Xu, Joseph R. Testa, Jianming Pei |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Heterozygote Cancer Research Pathology medicine.medical_specialty Genotype Tumor suppressor gene Laser Capture Microdissection Biology Article Germline Cancer syndrome Mice 03 medical and health sciences 0302 clinical medicine Germline mutation Neoplastic Syndromes Hereditary medicine Animals Genes Tumor Suppressor Genetic Predisposition to Disease Gene Knock-In Techniques Germ-Line Mutation Mice Knockout Comparative Genomic Hybridization BAP1 Reverse Transcriptase Polymerase Chain Reaction Tumor Suppressor Proteins Melanoma Cancer medicine.disease Immunohistochemistry Disease Models Animal 030104 developmental biology Oncology 030220 oncology & carcinogenesis Ubiquitin Thiolesterase |
| Zdroj: | Cancer Research. 76:2836-2844 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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