title: SMAD7 and MGMT genotype variants and cancer incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Study.
abstract: OBJECTIVE
  The SMAD7 gene was recently identified to be associated with colorectal cancer risk. Smad7 protein is a known inhibitor of TGF-β 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 (<mean 62 years), SMAD7 rs4464148 variant genotype group had higher HR of 1.71 (95%CI=1.03-2.83) compared to the non-variant genotype group.
  
  
  CONCLUSIONS
  These findings suggest that SMAD7 rs4464148 common variant genotype is associated with cancer incidence but not SMAD7 rs4939827, MGMT rs12917 or MGMT rs2308321. A combination of variants of the SMAD7 SNPs may be associated with increased cancer risk in this study population. However, these findings need to be replicated in larger studies and in studies of specific cancer sites.
authors.affiliation: MRC Centre for Nutritional Epidemiology in Cancer Prevention and Survival, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, United Kingdom. yet@srl.cam.ac.uk
authors.forename: Yet Hua
authors.initials: YH
authors.lastname: Loh
authors.forename: Panagiota N
authors.initials: PN
authors.lastname: Mitrou
authors.forename: Angela
authors.initials: A
authors.lastname: Wood
authors.forename: Robert N
authors.initials: RN
authors.lastname: Luben
authors.forename: Alison
authors.initials: A
authors.lastname: McTaggart
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Rodwell
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000453:epidemiology* / Q000208:ethnology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D051906:Smad7 Protein / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D006113:United Kingdom / Q000453:epidemiology; D044465:White People / Q000235:genetics
chemical_list: C497806:SMAD7 protein, human; D051906:Smad7 Protein; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes