Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer
Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer
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DOI：
10.1038/ng.982
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发表时间：
2011-12-01
期刊：
影响因子：
30.8
通讯作者：
Leung, Suet Yi
中科院分区：
文献类型：
--
作者：
Wang, Kai;Kan, Junsuo;Leung, Suet Yi
胃癌是一种异质性疾病，具有多种环境病因和多种致癌途径（1,2）。除了TP53的突变外，其他基因或通路的改变只占该疾病的一小部分。我们对22个胃癌样本进行了外显子组测序，发现了以前未报道的突变基因和通路改变；特别是，我们发现参与染色质修饰的基因通常发生突变。一项下游验证研究证实，ARID1A（编码SWI-SNF染色质重塑家族成员）在83%的微卫星不稳定性（MSI）、73%的eb病毒（EBV）感染和11%的未感染EBV和微卫星稳定（MSS）的胃癌患者中存在频繁的失活突变或蛋白缺乏。ARID1A的突变谱在胃癌分子亚型之间存在差异，突变流行率与TP53突变呈负相关。临床上，ARID1A的改变与更好的预后以分期无关的方式相关。这些结果揭示了基因组景观，并强调了染色质重塑在胃癌分子分类中的重要性。
Gastric cancer is a heterogeneous disease with multiple environmental etiologies and alternative pathways of carcinogenesis(1,2). Beyond mutations in TP53, alterations in other genes or pathways account for only small subsets of the disease. We performed exome sequencing of 22 gastric cancer samples and identified previously unreported mutated genes and pathway alterations; in particular, we found genes involved in chromatin modification to be commonly mutated. A downstream validation study confirmed frequent inactivating mutations or protein deficiency of ARID1A, which encodes a member of the SWI-SNF chromatin remodeling family, in 83% of gastric cancers with microsatellite instability (MSI), 73% of those with Epstein-Barr virus (EBV) infection and 11% of those that were not infected with EBV and microsatellite stable (MSS). The mutation spectrum for ARID1A differs between molecular subtypes of gastric cancer, and mutation prevalence is negatively associated with mutations in TP53. Clinically, ARID1A alterations were associated with better prognosis in a stage-independent manner. These results reveal the genomic landscape, and highlight the importance of chromatin remodeling, in the molecular taxonomy of gastric cancer.