Association between molecular subtypes of colorectal cancer and patient survival

Abstract

Background and aims: 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.

Keywords: Methylation; Oncogene; Prognostic Factor; Serrated Colorectal Cancer.

Figure 1

Kaplan-Meier survival curves comparing disease-specific survival in colorectal cancer patients by tumor subtype: type 1 (dashed black), type 2 (dotted black), type 3 (solid gray), type 4 (solid black), type 5 (dashed gray), some other tumor marker combination (dotted gray). Subtypes are defined as follows: type 1 = MSI-high, BRAF-mutated, KRAS-mutation negative, CIMP+; type 2 = MSS/MSI-low, BRAF-mutated, KRAS-mutation negative, CIMP+; type 3 = MSS/MSI-low, BRAF-mutation negative, KRAS-mutated, non-CIMP; type 4 = MSS/MSI-low, BRAF-mutation negative, KRAS-mutation negative, non-CIMP; type 5 = MSI-high, BRAF-mutation negative, KRAS-mutation negative, non-CIMP

Figure 2

Kaplan-Meier survival curves comparing overall survival in colorectal cancer patients by tumor subtype: type 1 (dashed black), type 2 (dotted black), type 3 (solid gray), type 4 (solid black), type 5 (dashed gray), some other tumor marker combination (dotted gray). Subtypes are defined as follows: type 1 = MSI-high, BRAF-mutated, KRAS-mutation negative, CIMP+; type 2 = MSS/MSI-low, BRAF-mutated, KRAS-mutation negative, CIMP+; type 3 = MSS/MSI-low, BRAF-mutation negative, KRAS-mutated, non-CIMP; type 4 = MSS/MSI-low, BRAF-mutation negative, KRAS-mutation negative, non-CIMP; type 5 = MSI-high, BRAF-mutation negative, KRAS-mutation negative, non-CIMP