title: Association between molecular subtypes of colorectal cancer and patient survival.
abstract: OBJECTIVE
  Colorectal cancer (CRC) is a heterogeneous disease that can develop via several pathways. Different CRC subtypes, identified based on tumor markers, have been proposed to reflect these pathways. We evaluated the significance of these previously proposed classifications to survival.
  
  
  METHODS
  Participants in the population-based Seattle Colon Cancer Family Registry were diagnosed with invasive CRC from 1998 through 2007 in western Washington State (N = 2706), and followed for survival through 2012. Tumor samples were collected from 2050 participants and classified into 5 subtypes based on combinations of tumor markers: type 1 (microsatellite instability [MSI]-high, CpG island methylator phenotype [CIMP] -positive, positive for BRAF mutation, negative for KRAS mutation); type 2 (microsatellite stable [MSS] or MSI-low, CIMP-positive, positive for BRAF mutation, negative for KRAS mutation); type 3 (MSS or MSI low, non-CIMP, negative for BRAF mutation, positive for KRAS mutation); type 4 (MSS or MSI-low, non-CIMP, negative for mutations in BRAF and KRAS); and type 5 (MSI-high, non-CIMP, negative for mutations in BRAF and KRAS). Multiple imputation was used to impute tumor markers for those missing data on 1-3 markers. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of subtypes with disease-specific and overall mortality, adjusting for age, sex, body mass, diagnosis year, and smoking history.
  
  
  RESULTS
  Compared with participants with type 4 tumors (the most predominant), participants with type 2 tumors had the highest disease-specific mortality (HR = 2.20, 95% CI: 1.47-3.31); subjects with type 3 tumors also had higher disease-specific mortality (HR = 1.32, 95% CI: 1.07-1.63). Subjects with type 5 tumors had the lowest disease-specific mortality (HR = 0.30, 95% CI: 0.14-0.66). Associations with overall mortality were similar to those with disease-specific mortality.
  
  
  CONCLUSIONS
  Based on a large, population-based study, CRC subtypes, defined by proposed etiologic pathways, are associated with marked differences in survival. These findings indicate the clinical importance of studies into the molecular heterogeneity of CRC.
authors.affiliation: Epidemiology Department, University of Washington, Seattle, Washington; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Electronic address: aiphipps@u.washington.edu.
authors.forename: Amanda I
authors.initials: AI
authors.lastname: Phipps
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Limburg
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.affiliation: Epidemiology Department, University of Washington, Seattle, Washington; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Burnett-Hartman
authors.affiliation: USC Epigenome Center, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisenberger
authors.affiliation: USC Epigenome Center, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Sinicrope
authors.affiliation: Cancer and Population Studies Group, Queensland Institute of Medical Research, Herston, QLD, Australia; Department of Molecular and Cellular Pathology, University of Queensland School of Medicine, Herston, QLD, Australia.
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.affiliation: Cancer and Population Studies Group, Queensland Institute of Medical Research, Herston, QLD, Australia.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.affiliation: Epidemiology Department, University of Washington, Seattle, Washington; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Centre for Public Health Research, Massey University, Wellington, New Zealand.
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.affiliation: Epidemiology Department, University of Washington, Seattle, Washington; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018899:CpG Islands; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012042:Registries; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014861:Washington; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: Methylation; Oncogene; Prognostic Factor; Serrated Colorectal Cancer