Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96816.
Department of Genetics, School of Medicine, Hyogo Medical University, Hyogo 663-8501, Japan.
Proc Natl Acad Sci U S A. 2024 Jul 16;121(29):e2405231121. doi: 10.1073/pnas.2405231121. Epub 2024 Jul 11.
We report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 ( gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we established in tissue culture from a patient carrying the heterozygous mutation. We found that these cells had genomic instability, reduced DNA repair, and impaired apoptosis. Investigating the underlying signaling pathways, we found that BARD1 forms a trimeric protein complex with p53 and SERCA2 that regulates calcium signaling and apoptosis. We validated these findings in -silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of activity and revealed that heterozygous germline mutations favor the development of mesothelioma and increase the susceptibility to asbestos carcinogenesis. These mesotheliomas are significantly less aggressive compared to mesotheliomas in asbestos workers.
我们报告称，约 1.8%的间皮瘤患者和 4.9%的 55 岁以下患者携带 BRCA1 相关 RING 结构域 1（基因的罕见种系变异，这些变异经计算分析预测为有害。我们对从携带杂合突变的患者组织培养中建立的原代成纤维细胞进行了功能测定，这对于正确解释错义变异至关重要。我们发现这些细胞具有基因组不稳定性、降低的 DNA 修复能力和受损的细胞凋亡。研究潜在的信号通路，我们发现 BARD1 与 p53 和 SERCA2 形成三聚体蛋白复合物，调节钙信号和细胞凋亡。我们在暴露于石棉的 -沉默的原代人胸膜细胞中验证了这些发现。我们的研究阐明了 活性的机制，并揭示了杂合种系 突变有利于间皮瘤的发展，并增加了对石棉致癌作用的易感性。与石棉工人中的间皮瘤相比，这些间皮瘤的侵袭性明显较低。
