PDF(Pubmed)
Abstract：
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 (BARD1) 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 BARD1V523A 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 BARD1-silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of BARD1 activity and revealed that heterozygous germline BARD1 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.
摘要：
我们报告说，所有间皮瘤患者中约有1.8％和55岁以下的患者中约有4.9％携带BRCA1相关RING域1（BARD1）基因的罕见种系变体，通过计算分析预测会造成损害。我们进行了功能分析,对于准确解释错义变体至关重要，我们在一名携带杂合BARD1V523A突变的患者的组织培养物中建立的原代成纤维细胞中。我们发现这些细胞具有基因组不稳定性，减少DNA修复，和凋亡受损。调查潜在的信号通路，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BARD1沉默的原代人中皮细胞中验证了这些发现。我们的研究阐明了BARD1活性的机制，并揭示了杂合种系BARD1突变有利于间皮瘤的发展并增加了对石棉致癌作用的敏感性。与石棉工人的间皮瘤相比，这些间皮瘤的侵袭性明显较低。
