Bayesian analysis of the rate of spontaneous malignant mesothelioma among BAP1 mutant mice in the absence of asbestos exposure

Our plain-English summary of Bayesian analysis of the rate of spontaneous malignant mesothelioma among BAP1 mutant mice in the absence of asbestos exposure, by D.M. Nielsen, M. Hsu, M. Zapata, et al (Scientific Reports, 2025).

The study

• Authors: D.M. Nielsen, M. Hsu, M. Zapata, G. Ciavarra, L. van Zyl
• Journal: Scientific Reports
• Published: 2025;15(1):169
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Cancers of the mesothelium, such as malignant mesothelioma (MM), historically have been attributed solely to exposure to asbestos. Recent large scale genetic and genomic functional studies now show that approximately 20% of all human mesotheliomas are causally linked to highly penetrant inherited (germline) pathogenic mutations in numerous cancer related genes. The rarity of these mutations in humans makes it difficult to perform statistically conclusive genetic studies to understand their biological effects. This has created a disconnect between functional and epidemiological studies. However, since the molecular pathogenesis of MM in mice accurately recapitulates that of human disease, this disconnect between functional and epidemiological studies can be overcome by using inbred mouse strains that harbor mutation(s) in genes involved in the disease. Most mouse studies have focused on the effect of asbestos exposure, leaving the effects of genetic mutations in the absence of exposure understudied. Here, using existing peer-reviewed studies, we investigate the rate of spontaneous MM among mice with and without germline genetic mutations, in the absence of asbestos exposure. We leveraged these published data to generate a historical control dataset (HCD) to allow us to improve statistical power and account for genetic heterogeneity between studies. Our Bayesian analyses indicate that the odds of spontaneous MM among germline BAP1 mutant mice is substantially larger than that of wildtype mice. These results support the existing biological study findings that mesotheliomas can arise in the presence of pathogenic germline mutations, independently of asbestos exposure.

© 2024. The Author(s).

In plain English

This article did not run a new experiment. The authors reanalyzed published mouse data, mainly the asbestos-unexposed arm of a 2016 study by Kadariya and colleagues. In that study, 2 of 93 mice carrying a germline BAP1 mutation developed malignant mesothelioma, and 0 of 43 wildtype mice did. Using that data alone, the authors' Bayesian analysis gave a 68.7% probability that the odds of mesothelioma were higher in the mutant mice. They then added unexposed, non-genetically-modified wildtype mice from six other published studies. Across the pooled wildtype data the article reports 8 cases in 8627 mice, giving an odds ratio of 23.1 (95% confidence interval 3.5–100.7) for the mutant mice. Methods that reduced the weight given to the outside studies, or that allowed rates to differ between studies, gave probabilities of 96.7% to 99.5% that the odds were higher in mutant mice. The authors concluded that their analysis agreed with biological data showing pathogenic germline BAP1 mutations are sufficient to cause mesothelioma without asbestos exposure. They noted that conditions may differ between studies and that the mutant group was small.

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: Statistical reanalysis (Bayesian) of previously published mouse data, adding a historical control dataset of wildtype mice drawn from other published studies; no new animals were studied
• Who was studied: Base data from the unexposed arm of Kadariya et al. (2016): 93 germline BAP1 mutant mice and 43 wildtype mice. Historical controls: wildtype, unexposed mice from six other published studies (Table 1).
• Exposure: No asbestos or other exogenous exposure. The factor compared was a germline BAP1 mutation (described in the discussion as heterozygous germline BAP1 null mutations) versus wildtype mice with no genetic modification.
• Main results:
  • Using only the Kadariya et al. base data, the probability that the odds ratio (BAP1 mutant vs wildtype mice) was greater than one was 68.7%, and greater than two was 47.4%.
  • In the pooled wildtype data (base data plus historical controls), 8 of 8627 (0.09%) unexposed wildtype mice had spontaneous mesothelioma.
  • Comparing the 2 of 93 BAP1 mutant mice with the pooled wildtype mice gave an odds ratio of 23.1 (95% confidence interval 3.5 to 100.7).
  • With the pooled wildtype data at full weight, the posterior probability that the odds ratio was greater than one was more than 99.9%, and greater than two was more than 99.8%.
  • With the historical controls down-weighted (power prior), the probability that the odds ratio was greater than one was 99.5%, and greater than two was 97.9%.
  • In the down-weighted analysis, the 95% credible interval for the probability of mesothelioma was 0.0002 to 0.0025 in wildtype mice and 0.0034 to 0.0630 in BAP1 mutant mice.
  • With a Bayesian beta-binomial meta-analysis allowing rates to vary between studies, the probability that the odds ratio was greater than one was 96.7%, and greater than two was 93.2%.
• The authors' conclusion: The authors concluded that their analysis agrees with biological data showing that pathogenic germline BAP1 mutations are sufficient to cause malignant mesothelioma independent of asbestos exposure.
• Limitations the authors state:
  • Combining data from earlier studies raises the problem that study conditions may differ between them.
  • The small number of BAP1 mutant mice in the base data gave much less certainty about their mesothelioma rate.
  • The normal approximation used in the weighting method may be less appropriate for rare events where zero cases may be observed.
  • When the historical controls were given little or no weight, one modeling approach gave highly diffuse results.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, BAP1, Asbestos Exposure, Mesothelium, Mesothelioma, Germline Mutation.

Related studies

• Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma — A. Napolitano, L. Pellegrini, et al. (2016)
• Dual Screen for Efficacy and Toxicity Identifies HDAC Inhibitor with Distinctive Activity Spectrum for BAP1-Mutant Uveal Melanoma — J.N. Kuznetsoff, D.A. Owens, et al. (2021)
• Absence of germline mutations in BAP1 in sporadic cases of malignant mesothelioma — S. Sneddon, J.S. Leon, et al. (2015)
• Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma — J. Xu, Y. Kadariya, et al. (2014)
• Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations — Y. Kadariya, M. Cheung, et al. (2016)
• BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos — F. Novelli, A. Bononi, et al. (2021)

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