title: A CpG island methylator phenotype of colorectal cancer that is contiguous with conventional adenomas, but not serrated polyps.
abstract: A subset of colorectal cancers (CRCs) harbor the CpG island methylator phenotype (CIMP), with concurrent multiple promoter hypermethylation of tumor-related genes. A serrated pathway in which CIMP is developed from serrated polyps is proposed. The present study characterized CIMP and morphologically examined precursor lesions of CIMP. In total, 104 CRCs treated between January 1996 and December 2004 were examined. Aberrant promoter methylation of 15 cancer-related genes was analyzed. CIMP status was classified according to the number of methylated genes and was correlated with the clinicopathological features, including the concomitant polyps in and around the tumors. The frequency of aberrant methylation in each CRC showed a bimodal pattern, and the CRCs were classified as CIMP-high (CIMP-H), CIMP-low (CIMP-L) and CIMP-negative (CIMP-N). CIMP-H was associated with aberrant methylation ofMLH1(P=0.005) and with an improved recurrence-free survival (RFS) rate following curative resection compared with CIMP-L/N (five-year RFS rate, 93.8 vs. 67.1%; P=0.044), while CIMP-N tumors were associated with frequent distant metastases at diagnosis (P=0.023). No concomitant serrated lesions were present in the tumors, whereas conventional adenoma was contiguous with 11 (10.6%) of 104 CRCs, including four CIMP-H CRCs. CIMP-H was classified in CRCs by a novel CIMP marker panel and the presence of concomitant tumors revealed that certain CIMP-H CRCs may have arisen from conventional adenomas.
authors.affiliation: Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Hokazono
authors.affiliation: Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ueki
authors.affiliation: Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Kinuko
authors.initials: K
authors.lastname: Nagayoshi
authors.affiliation: Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Nishioka
authors.affiliation: Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Tatsunobu
authors.initials: T
authors.lastname: Hatae
authors.affiliation: Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Koga
authors.affiliation: Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Hirahashi
authors.affiliation: Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
authors.affiliation: Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Tanaka
keywords: CpG island methylator phenotype; colorectal cancer; methylation; promoter CpG island; serrated pathway