Accumulation of DNA methylation is associated with tumor stage in gastric cancer
Accumulation of DNA methylation is associated with tumor stage in gastric cancer
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DOI：
10.1002/cncr.21754
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发表时间：
2006-03-15
期刊：
影响因子：
6.2
通讯作者：
Yasui, W
中科院分区：
文献类型：
--
作者：
Oue, N;Mitani, Y;Yasui, W
背景本研究的目的是阐明DNA甲基化基因高表达的胃癌（GC）与最初定义的CpG岛甲基化表型（CIMP）阳性的胃癌在临床病理特征上的差异。我们分析了12个肿瘤相关基因的DNA甲基化（hMLH1、MGMT、p16（INK4a）、CDH1、RAR-β、HLTF、RIZ1、TM、FLNc、LOX、HRASLS、HAND1），用甲基化特异性聚合酶链反应（PCR）和亚硫酸氢盐PCR检测10例健康青年正常胃粘膜组织。我们还通过PCR单链构象多态性检测5个MINT基因座的甲基化和p53突变状态来研究CIMP状态。我们通过定量逆转录PCR检测了50例胃癌患者中这12个基因的mRNA表达水平。每个肿瘤的平均甲基化基因数为4.83。每个基因的DNA甲基化与各自mRNA的低表达相关。在75个GC中，39个（52.0%）检测到高甲基化（5个或更多甲基化基因的GC）。75例胃癌中29例（37.8%）CIMP阳性。12个基因中的每一个的DNA甲基化在高甲基化组中比在低甲基化组中更频繁地观察到。6个特异性基因甲基化在CIMP阳性胃癌中的发生率高于CIMP阴性胃癌。其余6个基因的甲基化与CIMP状态无关。高甲基化在III/IV期胃癌（26/40例，65.0%）中的发生率高于I/II期胃癌（13/35例，37.0%）。1%，P = 0.029）。这些发现表明，具有较高数量的甲基化基因的GC具有比最初定义的CIMP阳性GC更明显的DNA甲基化谱。肿瘤相关基因的DNA甲基化随着肿瘤进展而积累。
BACKGROUND. The authors purpose in this study was to clarify the difference in terms of clinicopathologic features between gastric cancer (GC) with high numbers of DNA methylated genes and CpG island methylator phenotype (CIMP) -positive GC as originally defined.METHODS. We analyzed DNA methylation of 12 tumor-related genes (hMLH1, MGMT, p16(INK4a), CDH1, RAR-beta, HLTF, RIZ1, TM, FLNc, LOX, HRASLS, HAND1) in 75 samples of GC from 75 patients, 25 samples of corresponding nonneoplastic mucosa from 25 patients, and 10 samples of normal gastric mucosa from 10 healthy young individuals by methylation- specific polymerase chain reaction (PCR) and bisulfite PCR. We also investigated CIMP status by examining the methylation of five MINT loci and p53 mutation status by PCR single-strand conformation polymorphism. We measured levels of expression of mRNAs for these 12 genes by quantitative reverse transcription PCR in 50 GC specimens.RESULTS. The average number of methylated genes per tumor was 4.83. DNA methylation of each gene was correlated with low expression of the respective mRNA. High methylation (GC with 5 or more methylated genes) was detected in 39 (52.0%) of 75 GCs. Twenty-nine (37.8%) of 75 GCs were CIMP-positive. DNA methylation of each of the 12 genes was observed more frequently in the high-methylation group than in the low-methylation group. Methylation of 6 specific genes occurred more frequently in CIMP-positive GC than in CIMP-negative GC. Methylation of the remaining 6 genes was not correlated with CIMP-status. High methylation was found more frequently in Stage III/IV GC (26 of 40 cases, 65.0%) than in Stage I/II GC (13 of 35 cases, 37. 1%, P = 0.029).CONCLUSIONS. These findings indicate that GCs with higher numbers of methylated genes have more distinct DNA methylation profiles than the originally defined CIMP-positive GCs. DNA methylation of tumor-related genes accumulates in conjunction with tumor progression.