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.

BAP1, a tumor suppressor gene driving malignant mesothelioma

“…Similar phenotypic differences were observed between WT mice and two other Bap1 mutant mouse models in FVB background that harbor knock-in mutations analogous to the germline L and W mutations reported in humans (49). The median survival of asbestos injected W and L mice was significantly shorter than in WT mice (48 and 46 vs. 60 weeks, respectively).…”

“…Utilizing zinc-finger mediated genomic DNA modifications, we created three Bap1 mouse models (49,50). In the first study (50), a heterozygous Bap1-null model in the FVB mouse strain was created by introducing a deletion of exons 6 and 7.…”

“…Moreover, the incidence of MM development was at least 2-fold higher among the Bap1 knock-in mice compared to WT mice (74% and 71% vs. 35%, respectively). Interestingly, combining the data from all three mouse models (KO, L, and W) revealed that about two-thirds of the Bap1 mutant mice developed spontaneous tumors, with the majority of the tumors comprising ovarian sex cord stromal tumors (SCSTs) (49). Virtually all female mice developed SCST (some bilaterally) within 12-30 months of age.…”

Biomarkers in the prevention and follow-up of workers exposed to asbestos

“…These results were replicated 2 years later in 23% of MPM (51). Germline BAP1 mutation can be considered as "marker of susceptibility", not only for MPM but also for the development of a spectrum of tumour types, including some skin tumours (atypical benign melanocytic lesions, cutaneous melanoma, basal cell carcinoma), uveal melanoma, and some other cancers of the central nervous system, kidney, lung and breast (49). Micro-RNAs (miRNAs) are, 20-25 nucleotides long, non-coding RNA molecules, which regulate gene expression pairing with complementary sites of the correspondent mRNAs (52).…”

“…BAP1 might drive to cancer development because of its role in cell-cycle progression and tumour suppressing activity (47,48). The MPM prevalence in experimental model raised up to >70% in BAP1-mutant animals after asbestos exposure, in the face of a spontaneous rate of 2.2% in germinal mutant nonexposed (49). These data suggest that germline BAP1 mutations make individuals more susceptible to develop sporadic MPM and highly increase the asbestos-induced risk of pleural malignancy.…”