Methylation subtypes and large-scale epigenetic alterations in gastric cancer.
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.
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
Hermioni
H
Zouridis
Niantao
N
Deng
Tatiana
T
Ivanova
Yansong
Y
Zhu
Bernice
B
Wong
Dan
D
Huang
Yong Hui
YH
Wu
Yingting
Y
Wu
Iain Beehuat
IB
Tan
Natalia
N
Liem
Veena
V
Gopalakrishnan
Qin
Q
Luo
Jeanie
J
Wu
Minghui
M
Lee
Wei Peng
WP
Yong
Liang Kee
LK
Goh
Bin Tean
BT
Teh
Steve
S
Rozen
Patrick
P
Tan
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D049109:Cell Proliferation; D043171:Chromosomal Instability; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D000077209:Decitabine; D044127:Epigenesis, Genetic; D057890:Epigenomics; D005753:Gastric Mucosa / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D010641:Phenotype; D013274:Stomach Neoplasms / Q000235:genetics*
D000077209:Decitabine; D001374:Azacitidine