title: DNA methylation predicts recurrence from resected stage III proximal colon cancer.
abstract: 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.
authors.affiliation: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Joong Bae
authors.initials: JB
authors.lastname: Ahn
authors.forename: Woon Bok
authors.initials: WB
authors.lastname: Chung
authors.forename: Osamu
authors.initials: O
authors.lastname: Maeda
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Shin
authors.forename: Hyun Soo
authors.initials: HS
authors.lastname: Kim
authors.forename: Hyun Chul
authors.initials: HC
authors.lastname: Chung
authors.forename: Nam Kyu
authors.initials: NK
authors.lastname: Kim
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003110:Colonic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D019175:DNA Methylation; D018572:Disease-Free Survival; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012008:Recurrence; D018631:ras Proteins / Q000235:genetics*
chemical_list: D005819:Genetic Markers; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins