据2012年10月17日的《Science Translational Medicine》期刊报道，来自新加坡杜克-**大学医学研究生院(Duke-NUS Graduate Medical School)的研究人员鉴定出由环境因子触发的胃癌的多种新亚型。对胃癌复杂性的深入认识将有助于人们开发出更好的方法来治疗排在肺癌之后的世界上第二个主要癌症杀手，即胃癌。

　　论文通讯作者Patrick Tan博士说，“胃癌是一种异质性的疾病。每个胃癌病人经常对同一种疗法表现出明显不同的反应。改善胃癌临床结果将需要采用分子方法来把胃癌病人再分成生物学上类似的亚类，然后为每个亚类的病人设计出特异性的疗法。”

　　像很多癌症一样，胃癌是由基因突变导致的，但也由影响基因发挥作用的外在因子导致的。这些因子被称作表观遗传变化，通过甲基化发生作用。甲基化是一种在DNA上的被称作CpG位点的特异性位置加入一个甲基基团来修饰这些位点的化学过程。在无需改变DNA序列的情形下，甲基化沉默基因的行为。

　　在这项研究中，Tan和同事们利用240种原发性肿瘤和细胞系来首次充分地测量了胃癌的DNA甲基化谱，也被称作甲基化组(methylome)。他们的目标是在分子上鉴定出不是由主要基因突变导致的胃癌的新亚类。

　　研究人员发现胃癌甲基化组是广泛分布的：在分析的一半以上的CpG位点上，癌症都表现出发生改变的甲基化模式。很多甲基化变化与基因表达发生的显著性变化相关联，这就提示着甲基化变化可能在胃癌发展中发挥着功能上重要的作用。

　　研究人员也鉴定出胃癌中的一个具有极端高水平甲基化的亚类。人们之前就已提出CIMP(CpG Island Methylator Phenotype, CpG岛甲基化表型)亚类，但是它的临床重要性仍然是个谜。在这项研究中，研究人员证实存在CIMP亚类，而且将它与具有较差预后的年轻病人相关联起来。他们还在实验室实验中证实这些肿瘤可能对去甲基化药物具有增加的敏感性。

　　Tan说，“我们的研究结果强烈地证实胃癌并不是一种疾病，而是由多种疾病组成的一个集合体，并且每种疾病具有不同的生物学性质和标志性特征。如果胃癌是由多种相互作用因子(环境因素和遗传因素)产生的结果，那么我们需要更好的方法来诊断和治疗它。”

　　Methylation Subtypes and Large-Scale Epigenetic Alterations in Gastric Cancer

　　Hermioni Zouridis1,*,?, Niantao Deng1,2,*, Tatiana Ivanova1, Yansong Zhu1, Bernice Wong3, Dan Huang4, Yong Hui Wu1,5, Yingting Wu6,7, Iain Beehuat Tan2,8, Natalia Liem9, Veena Gopalakrishnan1, Qin Luo1, Jeanie Wu5, Minghui Lee5, Wei Peng Yong9,10, Liang Kee Goh1, Bin Tean Teh1,3,4, Steve Rozen6,11 and Patrick Tan

　　Epigenetic alterations are fundamental hallmarks of cancer genomes. We surveyed the landscape of DNA methylation alterations in gastric cancer by analyzing genome-wide CG dinucleotide (CpG) methylation profiles of 240 gastric cancers (203 tumors and 37 cell lines) and 94 matched normal gastric tissues. Cancer-specific epigenetic alterations were observed in 44% of CpGs, comprising both tumor hyper- and hypomethylation. Twenty-five percent of the methylation alterations were significantly associated with changes in tumor gene expression. Whereas most methylation-expression correlations were negative, several positively correlated methylation-expression interactions were also observed, associated with CpG sites exhibiting atypical transc**tion start site distances and gene body localization. Methylation clustering of the tumors revealed a CpG island methylator phenotype (CIMP) subgroup associated with widespread hypermethylation, young patient age, and adverse patient outcome in a disease stage–independent manner. CIMP cell lines displayed sensitivity to 5-aza-2′-deoxycytidine, a clinically approved demethylating drug. We also identified long-range regions of epigenetic silencing (LRESs) in CIMP tumors. Combined analysis of the methylation, gene expression, and drug treatment data suggests that certain LRESs may silence specific genes within the region, rather than all genes. Finally, we discovered regions of long-range tumor hypomethylation, associated with increased chromosomal instability. Our results provide insights into the epigenetic impact of environmental and biological agents on gastric epithelial cells, which may contribute to cancer.