Expansion of Gastric Intestinal Metaplasia with Copy Number Aberrations Contributes to Field Cancerization
Expansion of Gastric Intestinal Metaplasia with Copy Number Aberrations Contributes to Field Cancerization
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DOI：
10.1158/0008-5472.can-21-1523
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发表时间：
2022-05-01
期刊：
影响因子：
11.2
通讯作者：
Seno, Hiroshi
中科院分区：
文献类型：
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作者：
Kumagai, Ken;Shimizu, Takahiro;Seno, Hiroshi
肠上皮化生（IM）是幽门螺杆菌感染后发生胃癌的危险因素。为了探讨单纯胃IM对癌症发展的易感性，我们研究了单个IM胃腺的遗传改变。我们从11例粘膜内胃癌（IGC）患者和4例非IGC患者的发炎胃粘膜中分离出50个单个IM或非IM腺体;从我们的队列和先前的数据集中的11个个体的非发炎胃粘膜中分离出19个单个腺体作为对照。单个腺体的全外显子组测序显示，与非IM腺体相比，IM腺体内的各种基因中的体细胞突变的累积显著更高。克隆排序分析表明，IM腺体扩大，形成集群共享突变。此外，在来自26名IGC患者的96个成簇IM或非IM胃腺中进行靶向捕获深度测序和拷贝数（CN）分析。还对41个IGC样品和癌症基因组肿瘤-胃腺癌数据集进行CN分析。这些分析表明，多克隆扩增的IM通常获得CN畸变（CNA），包括染色体8，20和2的扩增。大部分的IM腺体簇通常由常见的CNA组成，而不是其他癌症相关的突变。此外，成簇IM腺体的CNA模式与IGC相似，提示癌前状态。综上所述，这些发现表明，在H. pylori感染时，IM腺体通过获得与IGC相当的CNA而扩大，有助于外地cancerization.Significance：这项研究有助于我们了解胃肠上皮化生作为胃腺癌的危险因素，通过其多灶性扩大和获得CNA和体细胞突变。
Intestinal metaplasia (IM) is a risk factor for gastric cancer following infection with Helicobacter pylori. To explore the sus-ceptibility of pure gastric IM to cancer development, we investigated genetic alterations in single IM gastric glands. We isolated 50 single IM or non-IM glands from the inflamed gastric mucosa of 11 patients with intramucosal gastric carcinoma (IGC) and 4 patients without IGC; 19 single glands in the noninflamed gastric mucosa of 11 individuals from our cohort and previous dataset were also included as controls. Whole-exome sequencing of single glands revealed significantly higher accumulation of somatic mutations in various genes within IM glands compared with non-IM glands. Clonal ordering analysis showed that IM glands expanded to form clusters with shared mutations. In addition, targeted-capture deep sequencing and copy number (CN) analyses were performed in 96 clustered IM or non-IM gastric glands from 26 patients with IGC. CN analyses were also performed on 41 IGC samples and The Cancer Genome Atlas-Stomach Adenocarcinoma datasets. These analyses revealed that polyclonally expanded IM commonly acquired CN aberrations (CNA), including amplification of chro-mosomes 8, 20, and 2. A large portion of clustered IM glands typically consisted of common CNAs rather than other cancer-related mutations. Moreover, the CNA patterns of clustered IM glands were similar to those of IGC, indicative of precancerous conditions. Taken together, these findings suggest that, in the gastric mucosa inflamed with H. pylori infection, IM glands expand via acquisition of CNAs comparable with those of IGC, contributing to field cancerization.Significance: This study contributes to our understanding of gastric intestinal metaplasia as a risk factor for gastric adenocarci-noma via their multifocal expansion and acquisition of CNAs and somatic mutations.