title: Lifetime alcohol intake is associated with an increased risk of KRAS+ and BRAF-/KRAS- but not BRAF+ colorectal cancer.
abstract: Ethanol in alcoholic beverages is a causative agent for colorectal cancer. Colorectal cancer is a biologically heterogeneous disease, and molecular subtypes defined by the presence of somatic mutations in BRAF and KRAS are known to exist. We examined associations between lifetime alcohol intake and molecular and anatomic subtypes of colorectal cancer. We calculated usual alcohol intake for 10-year periods from age 20 using recalled frequency and quantity of beverage-specific consumption for 38,149 participants aged 40-69 years from the Melbourne Collaborative Cohort Study. Cox regression was performed to derive hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between lifetime alcohol intake and colorectal cancer risk. Heterogeneity in the HRs across subtypes of colorectal cancer was assessed. A positive dose-dependent association between lifetime alcohol intake and overall colorectal cancer risk (mean follow-up = 14.6 years; n = 596 colon and n = 326 rectal cancer) was observed (HR = 1.08, 95% CI: 1.04-1.12 per 10 g/day increment). The risk was greater for rectal than colon cancer (phomogeneity= 0.02). Alcohol intake was associated with increased risks of KRAS+ (HR = 1.07, 95% CI: 1.00-1.15) and BRAF-/KRAS- (HR = 1.05, 95% CI: 1.00-1.11) but not BRAF+ tumors (HR = 0.89, 95% CI: 0.78-1.01; phomogeneity= 0.01). Alcohol intake is associated with an increased risk of KRAS+ and BRAF-/KRAS- tumors originating via specific molecular pathways including the traditional adenoma-carcinoma pathway but not with BRAF+ tumors originating via the serrated pathway. Therefore, limiting alcohol intake from a young age might reduce colorectal cancer originating via the traditional adenoma-carcinoma pathway.
authors.affiliation: Cancer Council Victoria, Cancer Epidemiology Centre, 615 St Kilda Road, Melbourne, VIC, 3004, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC, 3010, Australia.
authors.forename: Harindra
authors.initials: H
authors.lastname: Jayasekara
authors.affiliation: Cancer Council Victoria, Cancer Epidemiology Centre, 615 St Kilda Road, Melbourne, VIC, 3004, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC, 3010, Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: MacInnis
authors.affiliation: Farr Institute of Health Informatics Research, London, NW1 2DA, United Kingdom.|Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, United Kingdom.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Williamson
authors.affiliation: Cancer Council Victoria, Cancer Epidemiology Centre, 615 St Kilda Road, Melbourne, VIC, 3004, Australia.
authors.forename: Allison M
authors.identifier: 0000-0001-5464-2197
authors.initials: AM
authors.lastname: Hodge
authors.affiliation: Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.affiliation: Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.|Envoi Specialist Pathologists, Brisbane, QLD, Australia.|School of Medicine, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.affiliation: Cancer and Population Studies Group, Queensland Institute of Medical Research, Herston, QLD, Australia.
authors.forename: Rhiannon
authors.initials: R
authors.lastname: Walters
authors.affiliation: Centre for Alcohol Policy Research, La Trobe University, Melbourne, VIC, 3000, Australia.|Centre for Health Equity, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, VIC, 3010, Australia.|Centre for Social Research on Alcohol and Drugs, Stockholm University, Stockholm, SE-106 91, Sweden.
authors.forename: Robin
authors.initials: R
authors.lastname: Room
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC, 3010, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.affiliation: Cancer Council Victoria, Cancer Epidemiology Centre, 615 St Kilda Road, Melbourne, VIC, 3004, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC, 3010, Australia.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Milne
authors.affiliation: Cancer Council Victoria, Cancer Epidemiology Centre, 615 St Kilda Road, Melbourne, VIC, 3004, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC, 3010, Australia.
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.affiliation: Cancer Council Victoria, Cancer Epidemiology Centre, 615 St Kilda Road, Melbourne, VIC, 3004, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC, 3010, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC, 3010, Australia.|Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Daniel D
authors.identifier: 0000-0003-2225-6675
authors.initials: DD
authors.lastname: Buchanan
authors.affiliation: Cancer Council Victoria, Cancer Epidemiology Centre, 615 St Kilda Road, Melbourne, VIC, 3004, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC, 3010, Australia.
authors.forename: Dallas R
authors.initials: DR
authors.lastname: English
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000009:adverse effects*; D000437:Alcoholism / Q000150:complications; D000886:Anthropometry; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D011795:Surveys and Questionnaires
chemical_list: C117307:KRAS protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)
keywords: BRAF; KRAS; alcohol intake; colorectal cancer