Characteristic methylation profile in CpG island methylator phenotype-negative distal colorectal cancers.
Aberrant DNA methylation is involved in colon carcinogenesis. Although the CpG island methylator phenotype (CIMP) is defined as a subset of colorectal cancers (CRCs) with remarkably high levels of DNA methylation, it is not known whether epigenetic processes are also involved in CIMP-negative tumors. We analyzed the DNA methylation profiles of 94 CRCs and their corresponding normal-appearing colonic mucosa with 11 different markers, including the five classical CIMP markers. The CIMP markers were frequently methylated in proximal CRCs (p < 0.01); however, RASSF1A methylation levels were significantly higher in distal CRCs, the majority of which are CIMP-negative (p < 0.05). Similarly, methylation levels of RASSF1A and SFRP1 in the normal-appearing mucosae of distal CRC cases were significantly higher than those in the proximal CRC cases (p < 0.05). They were also positively correlated with age (RASSF1A, p < 0.01; SFRP1, p < 0.01). Microarray-based genome-wide DNA methylation analysis of 18 CRCs revealed that 168 genes and 720 genes were preferentially methylated in CIMP-negative distal CRCs and CIMP-positive CRCs, respectively. Interestingly, more than half of the hypermethylated genes in CIMP-negative distal CRCs were also methylated in the normal-appearing mucosae, indicating that hypermethylation in CIMP-negative distal CRCs is more closely associated with age-related methylation. By contrast, more than 60% of the hypermethylated genes in CIMP-positive proximal CRCs were cancer specific (p < 0.01). These data altogether suggest that CpG island promoters appear to be methylated in different ways depending on location, a finding which may imply the presence of different mechanisms for the acquisition of epigenetic changes during colon tumorigenesis.
Division of Molecular Oncology, Aichi Cancer Center Research Institute, Chikusa-Ku, Nagoya 464-8681, Japan.
Byonggu
B
An
Yutaka
Y
Kondo
Yasuyuki
Y
Okamoto
Keiko
K
Shinjo
Yukihide
Y
Kanemitsu
Koji
K
Komori
Takashi
T
Hirai
Akira
A
Sawaki
Masahiro
M
Tajika
Tsuneya
T
Nakamura
Kenji
K
Yamao
Yasushi
Y
Yatabe
Makiko
M
Fujii
Hideki
H
Murakami
Hirotaka
H
Osada
Tohru
T
Tani
Keitaro
K
Matsuo
Lanlan
L
Shen
Jean-Pierre J
JP
Issa
Yoshitaka
Y
Sekido
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D008875:Middle Aged; D010641:Phenotype