Association Between Molecular Subtypes of Colorectal Cancer and Patient Survival

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 148; no. 1; pp. 77 - 87.e2
• Main Authors: Phipps, Amanda I., Limburg, Paul J., Baron, John A., Burnett-Hartman, Andrea N., Weisenberger, Daniel J., Laird, Peter W., Sinicrope, Frank A., Rosty, Christophe, Buchanan, Daniel D., Potter, John D., Newcomb, Polly A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2015
• Subjects: Adult; Aged; Biomarkers, Tumor - genetics; Colorectal Neoplasms - genetics; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Colorectal Neoplasms - therapy; CpG Islands; Disease-Free Survival; DNA Methylation; DNA Mutational Analysis; Female; Gastroenterology and Hepatology; Genetic Predisposition to Disease; Humans; Kaplan-Meier Estimate; Male; Methylation; Microsatellite Instability; Middle Aged; Mutation; Oncogene; Phenotype; Prognostic Factor; Proportional Hazards Models; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Registries; Risk Factors; Serrated Colorectal Cancer; Time Factors; Treatment Outcome; Washington; Young Adult; MSI; Oncogene; CI; HR; MSS; SCCFR; Serrated Colorectal Cancer; PMR; CRC; CIMP; SEER; Methylation; Prognostic Factor; microsatellite instability; percentage of methylated reference; colorectal cancer; CpG island methylator phenotype; hazard ratio; confidence interval; Surveillance, Epidemiology, and End Results; microsatellite stable; Seattle Colon Cancer Family Registry
• ISSN: 0016-5085; 1528-0012; 1528-0012
• DOI: 10.1053/j.gastro.2014.09.038

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. 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. 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. 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.