Background:BAP1mutation carriers are predisposed to the development of mesothelioma. In mice, there is limited data and controversy about whether germlineBap1heterozygous mutations alone cause mesothelioma. However, a marked increase in mesothelioma incidence is observed inBap1-mutant mice upon even minimal asbestos exposures.Methods:To address this issue, we investigated spontaneous mesothelioma development over the lifetime of a large cohort ofBap1-mutant and wild-type (WT) mice across several genetic backgrounds. To determine if the incidence of mesotheliomas inBap1-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 forBap1-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 2/329Bap1-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 betweenBap1-mutant and WT mice.Conclusions:Based on these analyses, we cannot conclude that germlineBap1-mutant mice have a significantly increased risk of mesothelioma in the absence of asbestos exposure.
背景：BAP1基因突变携带者易患间皮瘤。在小鼠中，关于单纯种系Bap1杂合突变是否会导致间皮瘤的数据有限且存在争议。然而，即使仅暴露于极低剂量石棉，Bap1突变小鼠的间皮瘤发病率仍显著升高。 方法：为解决这一问题，我们在多种遗传背景下，对一大群Bap1突变小鼠和野生型（WT）小鼠进行了终生观察，研究其自发性间皮瘤的发生情况。为确定Bap1突变小鼠的间皮瘤发病率是否显著高于WT小鼠，我们采用频率学派和贝叶斯框架进行了统计分析。在贝叶斯框架中，为模拟疾病发生概率，对Bap1突变小鼠使用了无信息先验分布，而对WT组则基于涵盖动物整个生命周期的历史数据设定了信息性先验分布。我们采用多种策略整合历史数据并推导信息性先验，包括进行荟萃分析、假设历史数据集中间皮瘤发生概率一致，以及应用基于历史数据推导的贝叶斯荟萃分析预测先验。通过后验分布进行分析，并采用比值比、风险差和风险比进行比较。 结果：在不同遗传背景的小鼠中，自发性间皮瘤在329只Bap1突变小鼠中检出2例，227只WT小鼠中检出0例。采用四种统计方法分析，结果均未发现Bap1突变小鼠与WT小鼠的间皮瘤发生概率存在显著差异。 结论：基于这些分析，我们不能得出在无石棉暴露情况下，种系Bap1突变小鼠的间皮瘤风险显著增加的结论。
Spontaneous Mesotheliomas in GermlineBap1Heterozygous Mice from Different Genetic Backgrounds
肿瘤(癌症)患者之家