Nielsen Dahlia M, Hsu Mei, Zapata Michael, Ciavarra Giovanni, van Zyl Leonel
Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
ArrayXpress, Inc., Raleigh, NC, USA.
Sci Rep. 2025 Jan 2;15(1):169. doi: 10.1038/s41598-024-84069-w.
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.
间皮癌，如恶性间皮瘤（MM），在历史上一直被认为仅由接触石棉所致。近期大规模的基因和基因组功能研究表明，在所有人类间皮瘤中，约20%与众多癌症相关基因中的高外显率遗传性（种系）致病突变存在因果联系。这些突变在人类中极为罕见，使得难以开展具有统计学结论性的基因研究来了解其生物学效应。这导致了功能研究与流行病学研究之间的脱节。然而，由于小鼠MM的分子发病机制能够准确重现人类疾病的机制，因此可以通过使用在与疾病相关基因中携带突变的近交系小鼠品系来克服功能研究与流行病学研究之间的这种脱节。大多数小鼠研究聚焦于石棉暴露的影响，而在未暴露情况下基因突变的影响则研究不足。在此，我们利用现有的同行评审研究，调查在无石棉暴露情况下，有和没有种系基因突变的小鼠中自发性MM的发生率。我们利用这些已发表的数据生成一个历史对照数据集（HCD），以提高统计效力并考虑不同研究之间的基因异质性。我们的贝叶斯分析表明，种系BAP1突变小鼠发生自发性MM的几率显著高于野生型小鼠。这些结果支持了现有的生物学研究发现，即间皮瘤可在存在致病种系突变的情况下发生，与石棉暴露无关。
