Risk Factors and Incidence of Colorectal Cancer According to Major Molecular Subtypes. Issue 1 (7th October 2020)

• Record Type: Journal Article
• Authors: Wang, Liang; He, Xiaosheng; Ugai, Tomotaka; Haruki, Koichiro; Lo, Chun-Han; Hang, Dong; Akimoto, Naohiko; Fujiyoshi, Kenji; Wang, Molin; Fuchs, Charles S; Meyerhardt, Jeffrey A; Zhang, Xuehong; Wu, Kana; Chan, Andrew T; Giovannucci, Edward L; Ogino, Shuji; Song, Mingyang
• Is Part Of: JNCI cancer spectrum. Volume 5:Issue 1(2021)
• Publication Date: 2020-10-07
• DOI: 10.1093/jncics/pkaa089
• Languages: English
• ISSNs: 2515-5091

Abstract

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.