title: Promoter Methylation of CDO1 Identifies Clear-Cell Renal Cell Cancer Patients with Poor Survival Outcome.
abstract: OBJECTIVE
  In this era of molecular diagnostics, prediction of clear-cell renal cell cancer (ccRCC) survival requires optimization, as current prognostic markers fail to determine individual patient outcome. Epigenetic events are promising molecular markers. Promoter CpG island methylation of cysteine dioxygenase type 1 (CDO1), which was identified as prognostic marker for breast cancer, is studied as a potential marker for ccRCC survival.
  
  
  METHODS
  We collected primary tissues of 365 ccRCC cases identified within the prospective Netherlands Cohort Study (NLCS). In this population-based series, CDO1 promoter methylation was observed in 124 of 324 (38.3%) patients with successful methylation-specific PCR analysis. Kaplan-Meier curves and Wilcoxon tests were used to evaluate 10-year ccRCC-specific survival. Cox regression analysis was used to obtain crude and multivariate HRs and 95% confidence intervals (CI). The relative prognostic value of multivariate models with and without CDO1 promoter methylation was compared using likelihood-ratio tests.
  
  
  RESULTS
  Patients with CDO1 promoter methylation have a significantly poorer survival than those without (Wilcoxon P = 0.006). Differences in survival were independent of other prognostic factors, including age and sex (HR, 1.66; 95% CI, 1.12-2.45) and TNM stage, tumor size, and Fuhrman grade (HR, 1.89; 95% CI, 1.25-2.85). Multivariate models performed better with than without CDO1 promoter methylation status (likelihood-ratio P = 0.003). Survival curves were validated in an independent series of 280 ccRCC cases from The Cancer Genome Atlas (TCGA; Wilcoxon P < 0.001).
  
  
  CONCLUSIONS
  CDO1 promoter methylation may not substitute common prognostic makers to predict ccRCC survival, but offers additional, relevant prognostic information, indicating that it might be a novel molecular marker to determine ccRCC prognosis.
authors.affiliation: Department of Epidemiology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Ivette A G
authors.initials: IA
authors.lastname: Deckers
authors.affiliation: Department of Epidemiology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Schouten
authors.affiliation: Department of Pathology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Leander
authors.initials: L
authors.lastname: Van Neste
authors.affiliation: Department of Pathology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Iris J H
authors.initials: IJ
authors.lastname: van Vlodrop
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Patricia M M B
authors.initials: PM
authors.lastname: Soetekouw
authors.affiliation: Department of Pathology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Marcella M L L
authors.initials: MM
authors.lastname: Baldewijns
authors.affiliation: Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Jana
authors.initials: J
authors.lastname: Jeschke
authors.affiliation: Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Nita
authors.initials: N
authors.lastname: Ahuja
authors.affiliation: Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.affiliation: Department of Epidemiology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Piet A
authors.initials: PA
authors.lastname: van den Brandt
authors.affiliation: Department of Pathology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre, Maastricht, the Netherlands. manon.van.engeland@mumc.nl.
authors.forename: Manon
authors.initials: M
authors.lastname: van Engeland
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands / Q000235:genetics; D050558:Cysteine Dioxygenase / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor; C579734:CDO1 protein, human; D050558:Cysteine Dioxygenase