title: Methylation of serum DNA is an independent prognostic marker in colorectal cancer.
abstract: OBJECTIVE
  Aberrant CpG island hypermethylation is a feature of a subgroup of colorectal cancers, which can be detected in the serum of affected patients. This study was designed to identify methylation targets with prognostic significance in the serum of patients with colorectal cancer.
  
  
  METHODS
  In a gene evaluation set consisting of sera from 24 patients with local colorectal cancers, 14 with metastasized disease, and 20 healthy controls, the genes HPP1/TPEF, HLTF, and hMLH1 were identified as potential serum DNA methylation markers. These genes were further analyzed in a test set of sera of 104 patients with colorectal cancer.
  
  
  RESULTS
  Methylation of HLTF, HPP1/TPEF, and hMLH1 was found to be significantly correlated with tumor size, and methylation of HLTF and HPP1/TPEF was significantly associated with metastatic disease and tumor stage. Moreover, methylation of HPP1/TPEF was also associated with serum carcinoembryonic antigen. The prognostic relevance of methylation of these genes was tested in pretherapeutic sera of 77 patients with known follow-up. Patients with methylation of HPP1/TPEF or HLTF were found to have unfavorable prognosis (P = 0.001 and 0.008). In contrast, serum methylation of hMLH1 was not associated with a higher risk of death. Multivariate analysis showed methylated HPP1 and/or HLTF serum DNA to be independently associated with poor outcome and a relative risk of death of 3.4 (95% confidence interval, 1.4-8.1; P = 0.007).
  
  
  CONCLUSIONS
  These data show that the methylation status of specific genes in the serum of patients with colorectal cancer has the potential to become a pretherapeutic predictor of outcome.
authors.affiliation: Department of Medicine II, University Hospital Grosshadern, University of Munich, Munich, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Wallner
authors.forename: Andreas
authors.initials: A
authors.lastname: Herbst
authors.forename: Andrea
authors.initials: A
authors.lastname: Behrens
authors.forename: Alexander
authors.initials: A
authors.lastname: Crispin
authors.forename: Petra
authors.initials: P
authors.lastname: Stieber
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Rolf
authors.initials: R
authors.lastname: Lamerz
authors.forename: Frank T
authors.initials: FT
authors.lastname: Kolligs
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood; D002277:Carcinoma / Q000097:blood / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality; D015179:Colorectal Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm