title: MTHFR Glu429Ala and ERCC5 His46His polymorphisms are associated with prognosis in colorectal cancer patients: analysis of two independent cohorts from Newfoundland.
abstract: BACKGROUND
  In this study, 27 genetic polymorphisms that were previously reported to be associated with clinical outcomes in colorectal cancer patients were investigated in relation to overall survival (OS) and disease free survival (DFS) in colorectal cancer patients from Newfoundland.
  
  
  METHODS
  The discovery and validation cohorts comprised of 532 and 252 patients, respectively. Genotypes of 27 polymorphisms were first obtained in the discovery cohort and survival analyses were performed assuming the co-dominant genetic model. Polymorphisms associated with disease outcomes in the discovery cohort were then investigated in the validation cohort.
  
  
  RESULTS
  When adjusted for sex, age, tumor stage and microsatellite instability (MSI) status, four polymorphisms were independent predictors of OS in the discovery cohort MTHFR Glu429Ala (HR: 1.72, 95%CI: 1.04-2.84, p = 0.036), ERCC5 His46His (HR: 1.78, 95%CI: 1.15-2.76, p = 0.01), SERPINE1 -675indelG (HR: 0.52, 95%CI: 0.32-0.84, p = 0.008), and the homozygous deletion of GSTM1 gene (HR: 1.4, 95%CI: 1.03-1.92, p = 0.033). In the validation cohort, the MTHFR Glu429Ala polymorphism was associated with shorter OS (HR: 1.71, 95%CI: 1.18-2.49, p = 0.005), although with a different genotype than the discovery cohort (CC genotype in the discovery cohort and AC genotype in the validation cohort). When stratified based on treatment with 5-Fluorouracil (5-FU)-based regimens, this polymorphism was associated with reduced OS only in patients not treated with 5-FU. In the DFS analysis, when adjusted for other variables, the TT genotype of the ERCC5 His46His polymorphism was associated with shorter DFS in both cohorts (discovery cohort: HR: 1.54, 95%CI: 1.04-2.29, p = 0.032 and replication cohort: HR: 1.81, 95%CI: 1.11-2.94, p = 0.018).
  
  
  CONCLUSIONS
  In this study, associations of the MTHFR Glu429Ala polymorphism with OS and the ERCC5 His46His polymorphism with DFS were identified in two colorectal cancer patient cohorts. Our results also suggest that the MTHFR Glu429Ala polymorphism may be an adverse prognostic marker in patients not treated with 5-FU.
authors.affiliation: Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
authors.forename: Amit A
authors.initials: AA
authors.lastname: Negandhi
authors.forename: Angela
authors.initials: A
authors.lastname: Hyde
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Dicks
authors.forename: William
authors.initials: W
authors.lastname: Pollett
authors.forename: Banfield H
authors.initials: BH
authors.lastname: Younghusband
authors.forename: Patrick
authors.initials: P
authors.lastname: Parfrey
authors.forename: Roger C
authors.initials: RC
authors.lastname: Green
authors.forename: Sevtap
authors.initials: S
authors.lastname: Savas
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009523:Newfoundland and Labrador; D009687:Nuclear Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D011379:Prognosis; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics*; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005472:Fluorouracil; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5; C573423:MTHFR protein, human