據(jù)2012年10月17日的《Science Translational Medicine》期刊報(bào)道，來自新加坡杜克-**大學(xué)醫(yī)學(xué)研究生院(Duke-NUS Graduate Medical School)的研究人員鑒定出由環(huán)境因子觸發(fā)的胃癌的多種新亞型。對(duì)胃癌復(fù)雜性的深入認(rèn)識(shí)將有助于人們開發(fā)出更好的方法來治療排在肺癌之后的世界上第二個(gè)主要癌癥殺手，即胃癌。

　　論文通訊作者Patrick Tan博士說，“胃癌是一種異質(zhì)性的疾病。每個(gè)胃癌病人經(jīng)常對(duì)同一種療法表現(xiàn)出明顯不同的反應(yīng)。改善胃癌臨床結(jié)果將需要采用分子方法來把胃癌病人再分成生物學(xué)上類似的亞類，然后為每個(gè)亞類的病人設(shè)計(jì)出特異性的療法。”

　　像很多癌癥一樣，胃癌是由基因突變導(dǎo)致的，但也由影響基因發(fā)揮作用的外在因子導(dǎo)致的。這些因子被稱作表觀遺傳變化，通過甲基化發(fā)生作用。甲基化是一種在DNA上的被稱作CpG位點(diǎn)的特異性位置加入一個(gè)甲基基團(tuán)來修飾這些位點(diǎn)的化學(xué)過程。在無(wú)需改變DNA序列的情形下，甲基化沉默基因的行為。

　　在這項(xiàng)研究中，Tan和同事們利用240種原發(fā)性腫瘤和細(xì)胞系來首次充分地測(cè)量了胃癌的DNA甲基化譜，也被稱作甲基化組(methylome)。他們的目標(biāo)是在分子上鑒定出不是由主要基因突變導(dǎo)致的胃癌的新亞類。

　　研究人員發(fā)現(xiàn)胃癌甲基化組是廣泛分布的：在分析的一半以上的CpG位點(diǎn)上，癌癥都表現(xiàn)出發(fā)生改變的甲基化模式。很多甲基化變化與基因表達(dá)發(fā)生的顯著性變化相關(guān)聯(lián)，這就提示著甲基化變化可能在胃癌發(fā)展中發(fā)揮著功能上重要的作用。

　　研究人員也鑒定出胃癌中的一個(gè)具有極端高水平甲基化的亞類。人們之前就已提出CIMP(CpG Island Methylator Phenotype, CpG島甲基化表型)亞類，但是它的臨床重要性仍然是個(gè)謎。在這項(xiàng)研究中，研究人員證實(shí)存在CIMP亞類，而且將它與具有較差預(yù)后的年輕病人相關(guān)聯(lián)起來。他們還在實(shí)驗(yàn)室實(shí)驗(yàn)中證實(shí)這些腫瘤可能對(duì)去甲基化藥物具有增加的敏感性。

　　Tan說，“我們的研究結(jié)果強(qiáng)烈地證實(shí)胃癌并不是一種疾病，而是由多種疾病組成的一個(gè)集合體，并且每種疾病具有不同的生物學(xué)性質(zhì)和標(biāo)志性特征。如果胃癌是由多種相互作用因子(環(huán)境因素和遺傳因素)產(chǎn)生的結(jié)果，那么我們需要更好的方法來診斷和治療它。”

　　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.