Smoking and Colorectal Cancer Risk by Tumor Genetic and Epigenetic Subtypes: A Molecular Pathological Epidemiology (MPE) Study

Purpose: It remains to be investigated whether smoking is associated with colorectal carcinogenesis through specific epigenetic or genetic alterations, or abnormal protein expression. We comprehensively examined the influence of smoking on colorectal cancer risk by specific tumor molecular features, including epigenetic status (CpG island methylator phenotype [CIMP]), genomic instability (microsatellite instability [MSI]), oncogenic mutations (BRAF, KRAS, and PIK3CA), and tumor protein expressions (DNA methyltransferase-3B [DNMT3B], TP53, PTGS2 [cyclooxygenase-2], FASN, and CTNNB1 [b-catenin]). Methods: Follow-up of 134,204 individuals in two U.S. nationwide prospective cohorts (Nurses' Health Study [1980–2008] and Health Professionals Follow-up Study [1986–2008]) resulted in 1,292 incident rectal and colon cancers with available molecular data. Duplication method Cox proportional hazards model was used to calculate multivariate hazard ratio (HR) for developing a specific subtype of tumor according to smoking status. Results: Compared with never smokers, smoking of ≥40 cumulative pack-years was associated with increased risks for specific molecular types of colorectal cancer. Multivariate HRs are 2.12 for CIMP-high cancer (95% confidence interval [CI], 1.48- 3.03), 2.27 for MSI-high cancer (95% CI, 1.56–3.31), 2.00 for BRAF-mutated cancer (95% CI, 1.37–2.92), 1.37 for KRAS-wild-type cancer (95% CI, 1.12–1.68), 1.30 for PIK3CA-wild-type cancer (95% CI, 1.07–1.58), 1.33 for TP53-negative cancer (95% CI, 1.05–1.69), 1.37 for PTGS2-positive cancer (95% CI, 1.09–1.73), 1.36 for FASN-positive cancer (95% CI, 1.07–1.73), and 1.35 for CTNNB1-negative cancer (95% CI, 1.04–1.74). The influence of smoking significantly differed according to status of CIMP (P = 0.001 for heterogeneity test of CIMP-low vs. CIMP-high) and MSI (P = 0.0003 for heterogeneity test of MSS vs. MSI-high). There was no statistically significant differential association of smoking with other molecular subtypes. Conclusion: This molecular pathological epidemiology (MPE) study suggests that smoking might primarily cause epigenetic alterations, which lead to oncogenic mutations in colonic cells. The following are the 18 highest scoring abstracts of those submitted for presentation at the 37th Annual ASPO meeting held March 10–12, 2013, in Memphis, TN.