A Prospective Study of Duration of Smoking Cessation and Colorectal Cancer Risk by Epigenetics-related Tumor Classification

The effect of duration of cigarette smoking cessation on colorectal cancer risk by molecular subtypes remains unclear. Using duplication-method Cox proportional-hazards regression analyses, we examined associations between duration of smoking cessation and colorectal cancer risk according to status of CpG island methylator phenotype (CIMP), microsatellite instability, v-raf murine sarcoma viral oncogene homolog B1 ( BRAF ) mutation, or DNA methyltransferase-3B (DNMT3B) expression. Follow-up of 134,204 individuals in 2 US nationwide prospective cohorts (Nurses' Health Study (1980–2008) and Health Professionals Follow-up Study (1986–2008)) resulted in 1,260 incident rectal and colon cancers with available molecular data. Compared with current smoking, 10–19, 20–39, and ≥40 years of smoking cessation were associated with a lower risk of CIMP-high colorectal cancer, with multivariate hazard ratios (95% confidence intervals) of 0.53 (0.29, 0.95), 0.52 (0.32, 0.85), and 0.50 (0.27, 0.94), respectively ( P trend = 0.001), but not with the risk of CIMP-low/CIMP-negative cancer ( P trend = 0.25) ( P heterogeneity = 0.02, between CIMP-high and CIMP-low/CIMP-negative cancer risks). Differential associations between smoking cessation and cancer risks by microsatellite instability ( P heterogeneity = 0.02), DNMT3B expression ( P heterogeneity = 0.03), and BRAF ( P heterogeneity = 0.10) status appeared to be driven by the associations of CIMP-high cancer with microsatellite instability–high, DNMT3B-positive, and BRAF -mutated cancers. These molecular pathological epidemiology data suggest a protective effect of smoking cessation on a DNA methylation–related carcinogenesis pathway leading to CIMP-high colorectal cancer.