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DNA methylation predicts recurrence from resected stage III proximal colon cancer

 Joong Bae Ahn  ;  Woon Bok Chung  ;  Osamu Maeda  ;  Sang Joon Shin  ;  Hyun Soo Kim  ;  Hyun Chul Chung  ;  Nam Kyu Kim  ;  Jean-Pierre J. Issa 
 CANCER, Vol.117(9) : 1847-1854, 2011 
Journal Title
Issue Date
Adult ; Aged ; Aged, 80 and over ; Colonic Neoplasms/genetics* ; Colonic Neoplasms/mortality ; Colonic Neoplasms/pathology* ; DNA Methylation* ; Disease-Free Survival ; Female ; Genetic Markers ; Humans ; Male ; Microsatellite Instability ; Middle Aged ; Mutation ; Promoter Regions, Genetic ; Proto-Oncogene Proteins/genetics* ; Proto-Oncogene Proteins B-raf/genetics* ; Proto-Oncogene Proteins p21(ras) ; Recurrence ; ras Proteins/genetics*
colon cancer ; CpG island methylator phenotype ; LINE-1 ; methylation biomarker
BACKGROUND: In colorectal cancer (CRC), DNA methylation anomalies define distinct subgroups termed CpG island methylator phenotype 1 (CIMP1), CIMP2, and CIMP-negative. The role of this classification in predicting recurrence and disease-free survival (DFS) in resected stage III CRC was evaluated.

METHODS: Sporadic cancers from 161 patients were analyzed. Bisulfite pyrosequencing was used to examine the methylation of 2 global DNA methylation markers (LINE-1, Alu) and 9 loci (MINT1, MINT2, MINT31, P16, hMLH1, P14, SFRP1, SFRP2, and WNT5A). Mutations in BRAF and KRAS were assayed.

RESULTS: Gene hypermethylation clustered in discrete groups of patients, indicating the presence of CIMP. K-means clustering analysis identified 3 discrete subgroups: CIMP1 (n = 22, 13.7%), associated with proximal location and BRAF mutations; CIMP2 (n = 40, 24.8%), associated with KRAS mutations; and CIMP-negative (n = 99, 61.5%), associated with distal location. In proximal CRC, CIMP1 was correlated with a higher recurrence rate (53% for CIMP1, 18% for CIMP2, and 26% for CIMP-negative) and a worse DFS (P = .015). Also in proximal CRC, LINE-1 methylation was lower in patients whose cancer recurred compared with those whose cancer did not recur (P = .049). In multivariate analysis, CIMP1 and low LINE1 methylation were independent prognostic factors for DFS in proximal CRC (P = .008 for classification by K-means clustering analysis; P = .040 for LINE-1 methylation status).

CONCLUSIONS: DNA methylation is a useful biomarker of recurrence in resected stage III proximal but not distal CRC. However, as the number of CIMP1 cases was small in distal CRC, further study is required to validate our findings.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Nam Kyu(김남규) ORCID logo https://orcid.org/0000-0003-0639-5632
Shin, Sang Joon(신상준) ORCID logo https://orcid.org/0000-0001-5350-7241
Ahn, Joong Bae(안중배) ORCID logo https://orcid.org/0000-0001-6787-1503
Chung, Hyun Cheol(정현철) ORCID logo https://orcid.org/0000-0002-0920-9471
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