title: Analyses of 7,635 Patients with Colorectal Cancer Using Independent Training and Validation Cohorts Show That rs9929218 in CDH1 Is a Prognostic Marker of Survival.
abstract: OBJECTIVE
  Genome-wide association studies have identified numerous loci associated with colorectal cancer risk. Several of these have also been associated with patient survival, although none have been validated. Here, we used large independent training and validation cohorts to identify robust prognostic biomarkers for colorectal cancer.
  
  
  METHODS
  In our training phase, we analyzed 20 colorectal cancer-risk SNPs from 14 genome-wide associated loci, for their effects on survival in 2,083 patients with advanced colorectal cancer. A Cox survival model was used, stratified for treatment, adjusted for known prognostic factors, and corrected for multiple testing. Three SNPs were subsequently analyzed in an independent validation cohort of 5,552 colorectal cancer patients. A validated SNP was analyzed by disease stage and response to treatment.
  
  
  RESULTS
  Three variants associated with survival in the training phase; however, only rs9929218 at 16q22 (intron 2 of CDH1, encoding E-cadherin) was significant in the validation phase. Patients homozygous for the minor allele (AA genotype) had worse survival (training phase HR, 1.43; 95% confidence intervals; CI, 1.20-1.71, P = 5.8 × 10(-5); validation phase HR, 1.18; 95% CI, 1.01-1.37, P = 3.2 × 10(-2); combined HR, 1.28; 95% CI, 1.14-1.43, P = 2.2 × 10(-5)). This effect was independent of known prognostic factors, and was significant amongst patients with stage IV disease (P = 2.7 × 10(-5)). rs9929218 was also associated with poor response to chemotherapy (P = 3.9 × 10(-4)).
  
  
  CONCLUSIONS
  We demonstrate the potential of common inherited genetic variants to inform patient outcome and show that rs9929218 identifies approximately 8% of colorectal cancer patients with poor prognosis. rs9929218 may affect CDH1 expression and E-cadherin plays a role in epithelial-to-mesenchymal transition providing a mechanism underlying its prognostic potential. Clin Cancer Res; 21(15); 3453-61. ©2015 AACR.
authors: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors: Christopher G
authors: CG
authors: Smith
authors: MRC Clinical Trials Unit, Aviation House, London, United Kingdom.
authors: David
authors: D
authors: Fisher
authors: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors: Rebecca
authors: R
authors: Harris
authors: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.
authors: Timothy S
authors: TS
authors: Maughan
authors: Epidemiology Department, University of Washington, Seattle, Washington. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors: Amanda I
authors: AI
authors: Phipps
authors: Wellcome Trust Brenner Building, St James' University Hospital, University of Leeds, Leeds, United Kingdom.
authors: Susan
authors: S
authors: Richman
authors: Wellcome Trust Brenner Building, St James' University Hospital, University of Leeds, Leeds, United Kingdom.
authors: Matthew
authors: M
authors: Seymour
authors: Molecular and Population Genetics Laboratory and NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors: Ian
authors: I
authors: Tomlinson
authors: Molecular and Population Genetics Laboratory and NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors: Dan
authors: D
authors: Rosmarin
authors: Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, United Kingdom.
authors: David
authors: D
authors: Kerr
authors: Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Andrew T
authors: AT
authors: Chan
authors: Epidemiology Department, University of Washington, Seattle, Washington. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors: Ulrike
authors: U
authors: Peters
authors: Epidemiology Department, University of Washington, Seattle, Washington. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors: Polly A
authors: PA
authors: Newcomb
authors: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors: Shelley
authors: S
authors: Idziaszczyk
authors: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors: Hannah
authors: H
authors: West
authors: MRC Clinical Trials Unit, Aviation House, London, United Kingdom.
authors: Angela
authors: A
authors: Meade
authors: MRC Clinical Trials Unit, Aviation House, London, United Kingdom.
authors: Richard
authors: R
authors: Kaplan
authors: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom. cheadlejp@cardiff.ac.uk.
authors: Jeremy P
authors: JP
authors: Cheadle
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D014408:Biomarkers, Tumor / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins