DNA Methylation and Genetic Aberrations in Gastric Cancer
DNA Methylation and Genetic Aberrations in Gastric Cancer
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DOI：
10.1159/000511243
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发表时间：
2021-01-01
期刊：
影响因子：
3.2
通讯作者：
Kaneda, Atsushi
中科院分区：
文献类型：
--
作者：
Usui, Genki;Matsusaka, Keisuke;Kaneda, Atsushi
背景：胃癌（GC）是全球癌症相关死亡的主要原因之一。 GC是一种病理学和分子异质性疾病。启动子 CpG 岛中的 DNA 高甲基化会导致肿瘤抑制基因沉默，从而导致胃癌发生。此外，各种分子畸变，包括异常染色质结构、基因突变、结构变异和体细胞拷贝数改变，都与胃癌发生有关。摘要：全面的 DNA 甲基化分析揭示了 GC 中的多种 DNA 甲基化模式，并将 GC 分为不同的分子亚组：在与 Epstein-Barr 病毒 (EBV) 相关的 GC 中独特观察到的极高甲基化表观基因型、与微卫星不稳定性 (MSI) 相关的高甲基化表观基因型和低甲基化表观基因型。在癌症基因组图谱分类中，EBV和MSI被提取为GC的独立亚组，而其余GC被分为基因组稳定（GS）和染色体不稳定（CIN）亚组。 EBV 阳性 GC 在整个人类恶性肿瘤中表现出最极端的 DNA 高甲基化，经常表现出 CDKN2A 沉默、PIK3CA 突变、PD-L1/2 过表达和 TP53 突变缺乏。 MSI 表现出高 DNA 甲基化，通常具有 MLH1 沉默和丰富的基因突变。 GS 通常是弥漫型 GC，经常显示 CDH1/RHOA 突变或 CLDN18-ARHGAP 融合。 CIN 通常是肠型 GC，经常出现 TP53 突变和受体酪氨酸激酶基因组扩增。关键信息：遗传畸变的频率和目标因表观基因型而异。基因组和表观基因组的畸变预计会协同相互作用并促进胃癌的发生，对GC中的畸变进行全面分析可能有助于阐明癌发生的机制。
Background: Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. GC is a pathologically and molecularly heterogeneous disease. DNA hypermethylation in promoter CpG islands causes silencing of tumor-suppressor genes and thus contributes to gastric carcinogenesis. In addition, various molecular aberrations, including aberrant chromatin structures, gene mutations, structural variants, and somatic copy number alterations, are involved in gastric carcinogenesis. Summary: Comprehensive DNA methylation analyses revealed multiple DNA methylation patterns in GCs and classified GC into distinct molecular subgroups: extremely high-methylation epigenotype uniquely observed in GC associated with Epstein-Barr virus (EBV), high-methylation epigenotype associated with microsatellite instability (MSI), and low-methylation epigenotype. In The Cancer Genome Atlas classification, EBV and MSI are extracted as independent subgroups of GC, whereas the remaining GCs are categorized into genomically stable (GS) and chromosomal instability (CIN) subgroups. EBV-positive GC, exhibiting the most extreme DNA hypermethylation in the whole human malignancies, frequently shows CDKN2A silencing, PIK3CA mutations, PD-L1/2 overexpression, and lack of TP53 mutations. MSI, exhibiting high DNA methylation, often has MLH1 silencing and abundant gene mutations. GS is generally a diffuse-type GC and frequently shows CDH1/RHOA mutations or CLDN18-ARHGAP fusion. CIN is generally an intestinal-type GC and frequently has TP53 mutations and genomic amplification of receptor tyrosine kinases. Key Messages: The frequency and targets of genetic aberrations vary depending on the epigenotype. Aberrations in the genome and epigenome are expected to synergistically interact and contribute to gastric carcinogenesis and comprehensive analyses of those in GCs may help elucidate the mechanism of carcinogenesis.