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Cancer Res. 2016 May 1;76(9):2836-44. doi: 10.1158/0008-5472.CAN-15-3371. Epub 2016 Feb 19.

Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations.

Author information

1
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
2
Histopathology Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
3
Gene Expression and Regulation Program, Wistar Institute, Philadelphia, Pennsylvania.
4
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Histopathology Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
5
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. joseph.testa@fccc.edu.

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.

PMID:
26896281
PMCID:
PMC4873414
DOI:
10.1158/0008-5472.CAN-15-3371
[Indexed for MEDLINE]
Free PMC Article

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