title: MLH1 promoter methylation, diet, and lifestyle factors in mismatch repair deficient colorectal cancer patients from EPIC-Norfolk.
abstract: There is conflicting evidence for the role diet and lifestyle play in the development of mismatch repair (MMR)-deficient colorectal cancers (CRC). In this study, associations between MMR deficiency, clinicopathological characteristics, and dietary and lifestyle factors in sporadic CRC were investigated. Tumor samples from 185 individuals in the EPIC-Norfolk study were analyzed for MLH1 gene promoter methylation and microsatellite instability (MSI). Dietary and lifestyle data were collected prospectively using 7-day food diaries (7dd) and questionnaires. MMR-deficient tumor cases (MLH1 promoter methylation positive, MSI-H) were more likely to be female, older at diagnosis, early Dukes' stage (A/B), and proximal in location (MSI-H P = 0.03, 0.03, 0.02, and 0.001, respectively). Tumors with positive MLH1 promoter methylation (>20%) were associated with poor differentiation (P = 0.03). Low physical activity was associated with cases without MSI (P = 0.05). MMR deficiency was not significantly associated with cigarette smoking or alcohol, folate, fruit, vegetable, or meat consumption. We conclude that MMR-deficient tumors represent a distinct subset of sporadic CRC that are proximal in location, early Dukes' stage, and poorly differentiated, in cases that are female and older at diagnosis. There is no overall role for diet and lifestyle in MMR status in CRC, consistent with age-related susceptibility to MLH1 promoter methylation.
authors.affiliation: Medical Research Council Dunn Human Nutrition Unit, Cambridge, United Kingdom.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Gay
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
authors.forename: Panagiota N
authors.initials: PN
authors.lastname: Mitrou
authors.forename: Richard
authors.initials: R
authors.lastname: Bowman
authors.forename: Ashraf E
authors.initials: AE
authors.lastname: Ibrahim
authors.forename: Lisa
authors.initials: L
authors.lastname: Happerfield
authors.forename: Robert
authors.initials: R
authors.lastname: Luben
authors.forename: Alison
authors.initials: A
authors.lastname: McTaggart
authors.forename: Richard Y
authors.initials: RY
authors.lastname: Ball
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Rodwell
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D004032:Diet; D005260:Female; D005638:Fruit; D006801:Humans; D007150:Immunohistochemistry; D008019:Life Style; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D012907:Smoking; D011795:Surveys and Questionnaires; D006113:United Kingdom; D014675:Vegetables
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D004247:DNA; D000070957:MutL Protein Homolog 1