Methylation Subtypes and Large-Scale Epigenetic Alterations in Gastric Cancer

作     者：Zouridis, Hermioni Deng, Niantao Ivanova, Tatiana Zhu, Yansong Wong, Bernice Huang, Dan Wu, Yong Hui Wu, Yingting Tan, Iain Beehuat Liem, Natalia Gopalakrishnan, Veena Luo, Qin Wu, Jeanie Lee, Minghui Yong, Wei Peng Goh, Liang Kee Teh, Bin Tean Rozen, Steve Tan, Patrick 

作者机构：Cancer and Stem Cell Biology Program Duke-NUS Graduate Medical School 8 College Road Singapore 169857 Singapore. NUS Graduate School for Integrative Sciences and Engineering National University of Singapore 5 Lower Kent Ridge Road Singapore 119074 Singapore. National Cancer Centre Singapore–Van Andel Research Institute Translational Research Laboratory Department of Medical Sciences National Cancer Centre 11 Hospital Drive Singapore 169610 Singapore. Laboratory of Cancer Genetics Van Andel Research Institute Grand Rapids MI 49503 USA. Cellular and Molecular Research National Cancer Centre Singapore 169610 Singapore. Neuroscience and Behavioural Disorders Duke-NUS Graduate Medical School Singapore 169857 Singapore. Singapore-MIT Alliance National University of Singapore Singapore 119074 Singapore. Division of Medical Oncology National Cancer Centre Singapore 169610 Singapore. Cancer Science Institute of Singapore National University of Singapore Singapore 119074 Singapore. National Cancer Institute Singapore National University Hospital Singapore 119228 Singapore. Department of Psychiatry and Behavioral Sciences Duke University Medical Center Durham NC 27710 USA. Genome Institute of Singapore 60 Biopolis Street Genome 02-01 Singapore 138672 Singapore. 

出 版 物：《SCIENCE TRANSLATIONAL MEDICINE》 (Sci. Transl. Med.)

年 卷 期：2012年第4卷第156期

页      面：156ra140页

核心收录：

学科分类：0710[理学-生物学] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

基　　金：National Medical Research Council [TCR/001/2007] Biomedical Research Council [10/1/24/19/655] Duke-National University of Singapore Cancer Sciences Institute of Singapore 

摘      要：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 transcription 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.