Premium
Accumulation of DNA methylation is associated with tumor stage in gastric cancer
Author(s) -
Oue Naohide,
Mitani Yoshitsugu,
Motoshita Junichi,
Matsumura Shunji,
Yoshida Kazuhiro,
Kuniyasu Hiroki,
Nakayama Hirofumi,
Yasui Wataru
Publication year - 2006
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.21754
Subject(s) - methylation , dna methylation , microbiology and biotechnology , cpg site , gene , biology , polymerase chain reaction , bisulfite sequencing , cdh1 , epigenetics , illumina methylation assay , cancer research , gene expression , genetics , cell , cadherin
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). CONLUSIONS. 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. Cancer 2006. © 2006 American Cancer Society.