Spontaneous Mesotheliomas in Germline Bap1 Heterozygous Mice from Different Genetic Backgrounds

Background: BAP1 mutation carriers are predisposed to the development of mesothelioma. In mice, there is limited data and controversy about whether germline Bap1 heterozygous mutations alone cause mesothelioma. However, a marked increase in mesothelioma incidence is observed in Bap1-mutant mice upon even minimal asbestos exposures. Methods: To address this issue, we investigated spontaneous mesothelioma development over the lifetime of a large cohort of Bap1-mutant and wild-type (WT) mice across several genetic backgrounds. To determine if the incidence of mesotheliomas in Bap1-mutant mice is significantly increased compared to WT mice, we performed statistical analyses using frequentist and Bayesian frameworks. In the Bayesian framework, to model the probability of disease occurrence, a non-informative prior was used for Bap1-mutant mice, whereas an informative prior for the WT group was derived from historical data spanning the animals’ lifetimes. Multiple strategies were employed to incorporate historical data and infer the informative prior, including a meta-analysis, assuming a consistent probability of mesothelioma across historical datasets, and applying Bayesian meta-analytic predictive priors derived from historical data. Posterior distribution was used, and a comparison was made using odds ratio, risk difference, and risk ratio. Results: Spontaneous mesotheliomas were detected in 2/329 Bap1-mutant and 0/227 WT mice from various genetic backgrounds. Using four statistical approaches, the results did not detect a significant difference in the probabilities of mesothelioma occurrence between Bap1-mutant and WT mice.  Conclusions: Based on these analyses, we cannot conclude that germline Bap1-mutant mice have a significantly increased risk of mesothelioma in the absence of asbestos exposure.