SMAD7 and MGMT genotype variants and cancer incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Study

Purpose: The SMAD7 gene was recently identified to be associated with colorectal cancer risk. Smad7 protein is a known inhibitor of TGF-beta signalling pathway which has a prominent role in tumorigenesis. MGMT gene regulates the direct damage reversal repair pathway, preventing DNA damage and potential cancer development. This exploratory study aims to investigate the association between SMAD7 (rs4464148, rs4939827) and MGMT (rs12917, rs2308321) genotype variants, and all-cancer incidence. Methods: Our study population was a sub-cohort of the EPIC-Norfolk study, a prospective cohort of approximately 25,000 men and women aged 40-79. Between recruitment 1993-1997 and follow-up to 2006, 192 incident cases and 1155 non-cases with genotype data were identified. Baseline 7-day food diary and health/lifestyle questionnaire data were analysed. Results: SMAD7 rs4464148 variant genotype was associated with increased cancer incidence [HR = 1.34, 95%CI = 1.00-1.80] but no overall association for SMAD7 rs4939827 or MGMT genotypes. Participants with variant genotypes in both SMAD7 SNPs had a higher cancer incidence compared to those without any (HR = 2.74, 95%CI = 1.10-6.79) (P = 0.03; P(trend) = 0.01). Amongst the younger age participants (