title: Dietary, lifestyle and clinicopathological factors associated with APC mutations and promoter methylation in colorectal cancers from the EPIC-Norfolk study.
abstract: The tumour suppressor APC is the most commonly altered gene in colorectal cancer (CRC). Genetic and epigenetic alterations of APC may therefore be associated with dietary and lifestyle risk factors for CRC. Analysis of APC mutations in the extended mutation cluster region (codons 1276-1556) and APC promoter 1A methylation was performed on 185 archival CRC samples collected from participants of the European Prospective Investigation into Cancer (EPIC)-Norfolk study, with the aim of relating these to high-quality seven-day dietary and lifestyle data collected prospectively. Truncating APC mutations (APC(+) ) and promoter 1A methylation (PM(+) ) were identified in 43% and 23% of CRCs analysed, respectively. Distal CRCs were more likely than proximal CRCs to be APC(+) or PM(+) (p = 0.04). APC(+) CRCs were more likely to be moderately/well differentiated and microsatellite stable than APC(-) CRCs (p = 0.05 and 0.03). APC(+) CRC cases consumed more alcohol than their counterparts (p = 0.01) and PM(+) CRC cases consumed lower levels of folate and fibre (p = 0.01 and 0.004). APC(+) or PM(+) CRC cases consumed higher levels of processed meat and iron from red meat and red meat products (p = 0.007 and 0.006). Specifically, CRC cases harbouring GC-to-AT transition mutations consumed higher levels of processed meat (35 versus 24 g/day, p = 0.04) and iron from red meat and red meat products (0.8 versus 0.6 mg/day, p = 0.05). In a logistic regression model adjusted for age, sex and cigarette-smoking status, each 19 g/day (1SD) increment increase in processed meat consumption was associated with cases with GC-to-AT mutations (OR 1.68, 95% CI 1.03-2.75). In conclusion, APC(+) and PM(+) CRCs may be influenced by diet and GC-to-AT mutations in APC are associated with processed meat consumption, suggesting a mechanistic link with dietary alkylating agents, such as N-nitroso compounds.
authors.affiliation: Medical Research Council Dunn Human Nutrition Unit, Cambridge, UK.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Gay
authors.forename: Panagiota N
authors.initials: PN
authors.lastname: Mitrou
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keen
authors.forename: Richard
authors.initials: R
authors.lastname: Bowman
authors.forename: Adam
authors.initials: A
authors.lastname: Naguib
authors.forename: James
authors.initials: J
authors.lastname: Cooke
authors.forename: Gunter G
authors.initials: GG
authors.lastname: Kuhnle
authors.forename: Philip A
authors.initials: PA
authors.lastname: Burns
authors.forename: Robert
authors.initials: R
authors.lastname: Luben
authors.forename: Marleen
authors.initials: M
authors.lastname: Lentjes
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Richard Y
authors.initials: RY
authors.lastname: Ball
authors.forename: Ashraf Ek
authors.initials: AE
authors.lastname: Ibrahim
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000368:Aged; D000428:Alcohol Drinking / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D004032:Diet; D015930:Diet Records; D005060:Europe; D005260:Female; D006801:Humans; D008019:Life Style; D016015:Logistic Models; D008297:Male; D008460:Meat / Q000009:adverse effects; D008745:Methylation; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000502:physiology*; D011446:Prospective Studies; D012189:Retrospective Studies; D012907:Smoking / Q000009:adverse effects
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein