Identification of genes epigenetically silenced by CpG methylation in human gastric carcinoma
Identification of genes epigenetically silenced by CpG methylation in human gastric carcinoma
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DOI：
10.1016/j.ejca.2008.12.027
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发表时间：
2009-05-01
影响因子：
8.4
通讯作者：
Kim, Woo Ho
中科院分区：
文献类型：
--
作者：
Do Jee, Chang;Kim, Min A.;Kim, Woo Ho
为了鉴定胃癌中新的甲基化沉默基因，我们进行了全基因组搜索，寻找在用去甲基化剂 5-aza-2'-脱氧胞苷 (5Aza-dC) 治疗后上调的基因。当用 5Aza-dC 处理三种胃癌细胞系（SNU-1、-601 和 -719）时，使用寡核苷酸微阵列发现 143 个基因上调两倍或更多。其中 6 个基因，即 TFP12、GPX3、GPX1、IGFBP6、IRF7 和 DMRT1，在一种或多种胃癌细胞系中显示出启动子高甲基化，但通过亚硫酸氢盐测序和甲基化特异性 PCR 分析，在正常胃粘膜中未甲基化。在胃癌样本中发现以下百分比的这些基因被异常甲基化； TFP12 (80.9%)、GPX3 (30.1%)、DMRT1 (46.9%)、GPX1 (16.7%)、IGFBP6 (22.6%) 和 IRF7 (32.1%)。有趣的是，具有 TFPI2 甲基化等位基因的患者 (123/152, 80.9%) 的生存率低于具有未甲基化等位基因的患者 (p = 0.023)。多变量分析证实TFPI2甲基化是胃癌重要且独立的预后因素。此外，通过免疫组织化学在 566 个连续胃癌组织中证明，TFP12 表达的改变与性别 (p = 0.003)、WHO 分类 (p < 0.001) 和 Lauren 分类的混合亚型 (p < 0.001) 显着相关。因此，本研究鉴定了几个在胃癌中发生甲基化的新基因，其中，TFPI2 的甲基化是不利的预后标志物，(c) 2008 Elsevier Ltd. 保留所有权利。
To identify novel methylation-silenced genes in gastric cancer, we carried out a genome-wide search for genes that are up-regulated after treatment with the demethylating agent, 5-aza-2'-deoxycytidine (5Aza-dC). When three gastric cancer cell lines (SNU-1,-601, and -719) were treated with 5Aza-dC, 143 genes were found to be upregulated by twofold or more using oligonucleotide microarrays. Six of these genes, i.e. TFP12, GPX3, GPX1, IGFBP6, IRF7 and DMRT1, showed promoter hypermethylation in one or more gastric cancer cell lines, but were unmethylated in normal gastric mucosa by bisulphite sequencing and methylation-specific PCR analysis. The following percentages of these genes were found to be aberrantly methylated in gastric cancer samples; TFP12 (80.9%), GPX3 (30.1%), DMRT1 (46.9%), GPX1 (16.7%), IGFBP6 (22.6%) and IRF7 (32.1%). Interestingly, the survival of patients possessing methylated alleles of TFPI2 (123/152, 80.9%) was poorer than that of patients with unmethylated alleles (p = 0.023). Multivariate analysis confirmed that TFPI2 methylation is a significant and independent prognostic factor in gastric carcinoma. Furthermore, altered TFP12 expression, as demonstrated by immunohistochemistry in 566 consecutive gastric cancer tissues, was found to be significantly associated with sex (p = 0.003), WHO classification (p < 0.001), and a mixed subtype by Lauren's classification (p < 0.001). Thus, the present study identified several novel genes, which were methylated in gastric cancer and among them, methylation of TFPI2 was an unfavourable prognostic marker, (c) 2008 Elsevier Ltd. All rights reserved.