Cooperative participation of epigenomic and genomic alterations in the clinicopathological diversity of gastric adenocarcinomas: significance of cell adhesion and epithelial-mesenchymal transition-related signaling pathways.
Cooperative participation of epigenomic and genomic alterations in the clinicopathological diversity of gastric adenocarcinomas: significance of cell adhesion and epithelial-mesenchymal transition-related signaling pathways.
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DOI：
10.1093/carcin/bgaa079
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发表时间：
2020-11-13
期刊：
影响因子：
4.7
通讯作者：
Kanai Y
中科院分区：
文献类型：
--
作者：
Yang M;Arai E;Takahashi Y;Totsuka H;Chiku S;Taniguchi H;Katai H;Sakamoto H;Yoshida T;Kanai Y
本研究旨在阐明胃癌发生过程中表观基因组和基因组异常的协同作用。采用Infinium分析法对109例原发性胃腺癌患者的21例正常对照胃粘膜（C）、109例非癌胃粘膜（N）和105例癌组织（T）进行全基因组DNA甲基化分析。在这些样本中，66对N和相应的T样本进行全外显子组和单核苷酸多态性阵列分析。如我们先前的研究所示，109例患者在临床病理上分为最低侵袭性簇A（n = 20），最具侵袭性簇B1（n = 20）和簇B2（n = 69）。与C样本相比，即使在N样本中，每个聚类中的大多数DNA甲基化改变也已经发生，并且癌前N阶段的DNA甲基化改变由已建立的癌症本身遗传。导致ABCA 10、BNC 2、CDH 1、CTNNB 1、SMAD 4和VAV 2基因编码的蛋白质功能破坏的复发性单核苷酸变体和插入/缺失对簇B1具有特异性，而APC、EGFR、ERBB 2、ERBB 3、MLH 1和MUC 6基因的那些对簇A具有特异性。MetaCore通路分析显示，表观基因组影响的TWIST 1基因和基因组影响的CDH 1，CTNNB 1，MMP 9，TLN 2，ROCK 1和SMAD 4基因在Cluster B1中与细胞粘附，细胞骨架重塑和上皮-间质转化相关的信号通路中积累。这些数据表明，在癌前阶段的表观基因组的改变是重要的胃癌的发生和表观基因组和基因组的改变合作的胃腺癌的侵袭性的基础。全基因组分析显示，表观基因组影响的TWIST 1基因和基因组影响的CDH 1，CTNNB 1，MMP 9，TLN 2，ROCK 1，SMAD 4和VAV 2基因在侵袭性胃腺癌中与细胞粘附，细胞骨架重塑和上皮-间质转化相关的信号通路中协同积累。
The present study was conducted to clarify the cooperative significance of epigenomic and genomic abnormalities during gastric carcinogenesis. Using 21 samples of normal control gastric mucosa (C), 109 samples of non-cancerous gastric mucosa (N) and 105 samples of cancerous tissue (T) from 109 patients with primary gastric adenocarcinomas, genome-wide DNA methylation analysis was performed using Infinium assay. Among these samples, 66 paired N and corresponding T samples were subjected to whole-exome and single nucleotide polymorphism array analyses. As had been shown in our previous study, 109 patients were clustered clinicopathologically into least aggressive Cluster A (n = 20), most aggressive Cluster B1 (n = 20) and Cluster B2 (n = 69). Most DNA methylation alterations in each cluster had already occurred even in N samples compared with C samples, and DNA methylation alterations at the precancerous N stage were inherited by the established cancers themselves. Recurrent single nucleotide variants and insertions/deletions resulting in functional disruption of the proteins encoded by the ABCA10, BNC2, CDH1, CTNNB1, SMAD4 and VAV2 genes were specific to Cluster B1, whereas those of the APC, EGFR, ERBB2, ERBB3, MLH1 and MUC6 genes were specific to Cluster A. MetaCore pathway analysis revealed that the epigenomically affected TWIST1 gene and genomically affected CDH1, CTNNB1, MMP9, TLN2, ROCK1 and SMAD4 genes were accumulated in signaling pathways related to cell adhesion, cytoskeleton remodeling and epithelial–mesenchymal transition in Cluster B1. These data indicate that epigenomic alterations at the precancerous stage are important in gastric carcinogenesis and that epigenomic and genomic alterations cooperatively underlie the aggressiveness of gastric adenocarcinomas. Genome-wide analyses have revealed that the epigenomically affected TWIST1 gene and genomically affected CDH1, CTNNB1, MMP9, TLN2, ROCK1, SMAD4 and VAV2 genes cooperatively accumulate in signaling pathways related to cell adhesion, cytoskeleton remodeling and epithelial–mesenchymal transition in aggressive gastric adenocarcinomas.
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