title: Association of CHFR promoter methylation with disease recurrence in locally advanced colon cancer.
abstract: OBJECTIVE
  This study was designed to determine whether DNA methylation biomarkers are associated with recurrence and survival in colon cancer patients.
  
  
  METHODS
  A retrospective analysis of 82 patients who received curative surgical resection for American Joint Committee on Cancer (AJCC) high-risk stage II or III colon cancer (1999-2007) was conducted. DNA methylation status was quantitatively evaluated by the pyrosequencing method. We preselected three tumor suppressor genes and one locus of interest; CHFR, ID4, RECK, and MINT1. Mean methylation levels of multiple CpG sites in the promoter regions were used for analysis; 15% or more was defined as methylation positive. The association of recurrence-free survival (RFS) and overall survival (OS) with methylation status was analyzed by the log-rank test, Kaplan-Meier method, and Cox proportional hazards model.
  
  
  RESULTS
  Methylation levels of ID4, MINT1, and RECK did not correlate with RFS or OS. CHFR was methylation positive in 63% patients. When methylation status was dichotomized (negative or low: <30%, high: ≥30%), patients with CHFR methylation-high (44%) had worse RFS (P = 0.006) and reduced OS (P = 0.069). When stratified by stage, CHFR methylation-high was associated with reduced RFS (P = 0.004) and OS (P = 0.010) in stage III patients. CHFR methylation-high was commonly associated with N2 disease (P = 0.04) and proximal tumors (P = 0.002). Multivariate analysis indicated AJCC T4 disease and CHFR methylation-high (P = 0.001 and P = 0.015, respectively) were independent predictors for recurrence.
  
  
  CONCLUSIONS
  The extent of CHFR promoter methylation correlates with RFS, indicating it is a promising epigenetic marker for recurrence.
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Motofumi
authors.initials: M
authors.lastname: Tanaka
authors.forename: Ping
authors.initials: P
authors.lastname: Chang
authors.forename: Yanan
authors.initials: Y
authors.lastname: Li
authors.forename: Donghui
authors.initials: D
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Overman
authors.forename: Dipen M
authors.initials: DM
authors.lastname: Maru
authors.forename: Salil
authors.initials: S
authors.lastname: Sethi
authors.forename: Jonathan
authors.initials: J
authors.lastname: Phillips
authors.forename: Gail L
authors.initials: GL
authors.lastname: Bland
authors.forename: James L
authors.initials: JL
authors.lastname: Abbruzzese
authors.forename: Cathy
authors.initials: C
authors.lastname: Eng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012008:Recurrence; D012189:Retrospective Studies; D016019:Survival Analysis; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases; D000070957:MutL Protein Homolog 1