Risk Factors and Incidence of Colorectal Cancer According to Major Molecular Subtypes

Abstract

Background: Colorectal cancer (CRC) is a heterogeneous disease that can develop via 3 major pathways: conventional, serrated, and alternate. We aimed to examine whether the risk factor profiles differ according to pathway-related molecular subtypes.

Methods: We examined the association of 24 risk factors with 4 CRC molecular subtypes based on a combinatorial status of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and BRAF and KRAS mutations by collecting data from 2 large US cohorts. We used inverse probability weighted duplication-method Cox proportional hazards regression to evaluate differential associations across subtypes.

Results: We documented 1175 CRC patients with molecular subtype data: subtype 1 (n = 498; conventional pathway; non-MSI-high, CIMP-low or negative, BRAF-wild-type, KRAS-wild-type), subtype 2 (n = 138; serrated pathway; any MSI status, CIMP-high, BRAF-mutated, KRAS-wild-type), subtype 3 (n = 367; alternate pathway; non-MSI-high, CIMP-low or negative, BRAF-wild-type, KRAS-mutated), and subtype 4 (n = 172; other marker combinations). Statistically significant heterogeneity in associations with CRC subtypes was found for age, sex, and smoking, with a higher hazard ratio (HR) observed for the subtype 2 (HR per 10 years of age = 2.64, 95% CI = 2.13 to 3.26; HR for female = 2.65, 95% CI = 1.60 to 4.39; HR per 20-pack-year of smoking = 1.29, 95% CI = 1.14 to 1.45) than other CRC subtypes (all P _{heterogeneity} < .005). A stronger association was found for adiposity measures with subtype 1 CRC in men and subtype 3 CRC in women and for several dietary factors with subtype 1 CRC, although these differences did not achieve statistical significance at α level of .005.

Conclusions: Risk factor profiles may differ for CRC arising from different molecular pathways.

Figure 1.

Subsite distribution and risk factor profiles of colorectal cancer (CRC) according to molecular subtypes. The bottom panels demonstrate risk factors that had a particularly stronger association with a specific subtype of CRC compared with other subtypes. For CRC subsites, tumors with missing subsite information are not included in the pie charts. ^†Dietary factors include less whole grains intake, less cereal fiber intake, less vitamin D intake, less folate intake, less calcium intake, higher total red meat intake, higher processed red meat intake, and higher unprocessed red meat intake. BMI = body mass index; CIMP = CpG island methylator phenotype; CRC = colorectal cancer; MSI = microsatellite instability.