Spontaneous Mesotheliomas in Germline Bap1 Heterozygous Mice from Different Genetic Backgrounds

Our plain-English summary of Spontaneous Mesotheliomas in Germline Bap1 Heterozygous Mice from Different Genetic Backgrounds, by Y. Kadariya, L. Zhang, E. Sementino, et al (Cancers, 2025).

The study

• Authors: Y. Kadariya, L. Zhang, E. Sementino, E. Ross, J.R. Testa
• Journal: Cancers
• Published: 2025;17(16)
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This animal experiment asked whether mice born with one damaged copy of the Bap1 gene develop mesothelioma on their own, without asbestos. The authors followed 329 Bap1-mutant mice and 227 normal (wild-type) littermates for their whole lives, in three genetic backgrounds (FVB/N, 129/Sv and C57BL/6). The 329 included 93 mutant mice from the authors' earlier 2016 report. The mice were housed without asbestos exposure. Two of the 329 mutant mice developed mesothelioma, both FVB/N mice from the earlier cohort, compared with 0 of 227 wild-type mice. Fisher's exact test gave a p-value of 0.516. Three Bayesian analyses that also used published lifetime data on wild-type mice found no statistically significant difference. In one of them, the 95% credible interval for the odds ratio ran from 0.68 to 188. That analysis put the probability that the odds ratio exceeded 2 at 83%. The authors said the wide intervals reflected how rare mesothelioma was in both groups. They concluded they cannot conclude that these mice have an increased risk of spontaneous mesothelioma compared with wild-type mice.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment: lifetime observation of genetically engineered mice with germline Bap1 heterozygous mutations and their wild-type littermates, analysed with Fisher's exact test and three Bayesian approaches that drew on historical wild-type mouse data
• Who was studied: 329 germline Bap1 heterozygous mice and 227 wild-type littermates in FVB/N, 129/Sv and C57BL/6 backgrounds, including one C57BL/6 model from Genentech. The 329 comprised 93 mutant mice from the authors' 2016 report, followed to end of life, plus 236 new mutant mice.
• Exposure: No asbestos exposure. The factor studied was a germline Bap1 heterozygous mutation (knockout or knock-in), compared with no mutation.
• Main results:
  • Across all genetic backgrounds, 2 of 329 Bap1-mutant mice and 0 of 227 wild-type mice developed mesothelioma.
  • Both mesotheliomas were in FVB/N Bap1-mutant mice. None occurred in Bap1-mutant mice in C57BL/6 or 129/Sv backgrounds.
  • Fisher's exact test comparing Bap1-mutant and wild-type mice gave p = 0.516, which the authors described as no statistically significant difference.
  • In the Bayesian analysis assuming the same mesothelioma rate across historical wild-type data, the 95% credible interval for the odds ratio (Bap1-mutant vs wild-type) was 0.68 to 188, with a similar range for the risk ratio.
  • In the same analysis, the mean risk difference (Bap1-mutant minus wild-type) was 0.007, with a 95% credible interval from minus 0.00134 to 0.01946.
  • The posterior probability that the odds ratio exceeded 2 was 83%.
  • The posterior probability that the odds ratio exceeded 5 was 57%. The authors said these probabilities suggest increased risk in Bap1-mutant mice, but because of the wide credible intervals they could not conclude an association.
  • If Bap1-mutant and wild-type mice had the same rate, simulations gave a 13% probability of seeing two or more mesotheliomas among 329 mice.
  • Using a prior derived from meta-analysis of historical data, the mean risk difference was 0.0068 (95% credible interval minus 0.003 to 0.0198).
  • Using meta-analytic predictive priors, the mean risk difference was 0.0062 (95% credible interval minus 0.003 to 0.019).
• The authors' conclusion: The authors concluded that they cannot conclude that germline Bap1 heterozygous mice have an increased risk of spontaneous mesothelioma compared to wild-type mice.
• Limitations the authors state:
  • Mesothelioma was rare in both groups, which led to wide intervals and substantial uncertainty in the estimated ratios.
  • Genetically engineered mouse models do not necessarily reproduce the human disease.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, BAP1, Asbestos Exposure, Meta-Analysis, Odds Ratio.

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