title: Alcohol, one-carbon nutrient intake, and risk of colorectal cancer according to tumor methylation level of IGF2 differentially methylated region.
abstract: BACKGROUND
  Although a higher consumption of alcohol, which is a methyl-group antagonist, was previously associated with colorectal cancer risk, mechanisms remain poorly understood.
  
  
  OBJECTIVE
  We hypothesized that excess alcohol consumption might increase risk of colorectal carcinoma with hypomethylation of insulin-like growth factor 2 (IGF2) differentially methylated region-0 (DMR0), which was previously associated with a worse prognosis.
  
  
  METHODS
  With the use of a molecular pathologic epidemiology database in 2 prospective cohort studies, the Nurses' Health Study and Health Professionals Follow-up Study, we examined the association between alcohol intake and incident colorectal cancer according to the tumor methylation level of IGF2 DMR0. Duplication-method Cox proportional cause-specific hazards regression for competing risk data were used to compute HRs and 95% CIs. In addition, we investigated intakes of vitamin B-6, vitamin B-12, methionine, and folate as exposures.
  
  
  RESULTS
  During 3,206,985 person-years of follow-up, we identified 993 rectal and colon cancer cases with an available tumor DNA methylation status. Compared with no alcohol consumption, the consumption of ≥15 g alcohol/d was associated with elevated risk of colorectal cancer with lower levels of IGF2 DMR0 methylation [within the first and second quartiles: HRs of 1.55 (95% CI: 1.08, 2.24) and 2.11 (95% CI: 1.44, 3.07), respectively]. By contrast, alcohol consumption was not associated with cancer with higher levels of IGF2 DMR0 methylation. The association between alcohol and cancer risk differed significantly by IGF2 DMR0 methylation level (P-heterogeneity = 0.006). The association of vitamin B-6, vitamin B-12, and folate intakes with cancer risk did not significantly differ according to IGF2 DMR0 methylation level (P-heterogeneity > 0.2).
  
  
  CONCLUSIONS
  Higher alcohol consumption was associated with risk of colorectal cancer with IGF2 DMR0 hypomethylation but not risk of cancer with high-level IGF2 DMR0 methylation. The association between alcohol intake and colorectal cancer risk may differ by tumor epigenetic features.
authors.affiliation: From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, MY, KM, YS, SAK, KI, CSF, and SO); the Departments of Nutrition (RN, KW, and ELG), Epidemiology (MW, ELG, SO, and ESS), and Biostatistics (MW), Harvard School of Public Health, Boston, MA; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (MW, XZ, KW, ELG, ATC, CSF, and ESS); the Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan (YB); the Division of Gastroenterology, Massachusetts General Hospital, Boston, MA (ATC); and Applied Cancer Research-Institution for Translational Research Vienna, Vienna, Austria (ESS).
authors.forename: Reiko
authors.initials: R
authors.lastname: Nishihara
authors.affiliation: From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, MY, KM, YS, SAK, KI, CSF, and SO); the Departments of Nutrition (RN, KW, and ELG), Epidemiology (MW, ELG, SO, and ESS), and Biostatistics (MW), Harvard School of Public Health, Boston, MA; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (MW, XZ, KW, ELG, ATC, CSF, and ESS); the Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan (YB); the Division of Gastroenterology, Massachusetts General Hospital, Boston, MA (ATC); and Applied Cancer Research-Institution for Translational Research Vienna, Vienna, Austria (ESS).
authors.forename: Molin
authors.initials: M
authors.lastname: Wang
authors.affiliation: From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, MY, KM, YS, SAK, KI, CSF, and SO); the Departments of Nutrition (RN, KW, and ELG), Epidemiology (MW, ELG, SO, and ESS), and Biostatistics (MW), Harvard School of Public Health, Boston, MA; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (MW, XZ, KW, ELG, ATC, CSF, and ESS); the Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan (YB); the Division of Gastroenterology, Massachusetts General Hospital, Boston, MA (ATC); and Applied Cancer Research-Institution for Translational Research Vienna, Vienna, Austria (ESS).
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
authors.affiliation: From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, MY, KM, YS, SAK, KI, CSF, and SO); the Departments of Nutrition (RN, KW, and ELG), Epidemiology (MW, ELG, SO, and ESS), and Biostatistics (MW), Harvard School of Public Health, Boston, MA; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (MW, XZ, KW, ELG, ATC, CSF, and ESS); the Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan (YB); the Division of Gastroenterology, Massachusetts General Hospital, Boston, MA (ATC); and Applied Cancer Research-Institution for Translational Research Vienna, Vienna, Austria (ESS).
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.affiliation: From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, MY, KM, YS, SAK, KI, CSF, and SO); the Departments of Nutrition (RN, KW, and ELG), Epidemiology (MW, ELG, SO, and ESS), and Biostatistics (MW), Harvard School of Public Health, Boston, MA; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (MW, XZ, KW, ELG, ATC, CSF, and ESS); the Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan (YB); the Division of Gastroenterology, Massachusetts General Hospital, Boston, MA (ATC); and Applied Cancer Research-Institution for Translational Research Vienna, Vienna, Austria (ESS).
authors.forename: Mai
authors.initials: M
authors.lastname: Yamauchi
authors.affiliation: From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, MY, KM, YS, SAK, KI, CSF, and SO); the Departments of Nutrition (RN, KW, and ELG), Epidemiology (MW, ELG, SO, and ESS), and Biostatistics (MW), Harvard School of Public Health, Boston, MA; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (MW, XZ, KW, ELG, ATC, CSF, and ESS); the Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan (YB); the Division of Gastroenterology, Massachusetts General Hospital, Boston, MA (ATC); and Applied Cancer Research-Institution for Translational Research Vienna, Vienna, Austria (ESS).
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mima
authors.affiliation: From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, MY, KM, YS, SAK, KI, CSF, and SO); the Departments of Nutrition (RN, KW, and ELG), Epidemiology (MW, ELG, SO, and ESS), and Biostatistics (MW), Harvard School of Public Health, Boston, MA; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (MW, XZ, KW, ELG, ATC, CSF, and ESS); the Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan (YB); the Division of Gastroenterology, Massachusetts General Hospital, Boston, MA (ATC); and Applied Cancer Research-Institution for Translational Research Vienna, Vienna, Austria (ESS).
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Sukawa
authors.affiliation: From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, MY, KM, YS, SAK, KI, CSF, and SO); the Departments of Nutrition (RN, KW, and ELG), Epidemiology (MW, ELG, SO, and ESS), and Biostatistics (MW), Harvard School of Public Health, Boston, MA; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (MW, XZ, KW, ELG, ATC, CSF, and ESS); the Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan (YB); the Division of Gastroenterology, Massachusetts General Hospital, Boston, MA (ATC); and Applied Cancer Research-Institution for Translational Research Vienna, Vienna, Austria (ESS).
authors.forename: Sun A
authors.initials: SA
authors.lastname: Kim
authors.affiliation: From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, MY, KM, YS, SAK, KI, CSF, and SO); the Departments of Nutrition (RN, KW, and ELG), Epidemiology (MW, ELG, SO, and ESS), and Biostatistics (MW), Harvard School of Public Health, Boston, MA; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (MW, XZ, KW, ELG, ATC, CSF, and ESS); the Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan (YB); the Division of Gastroenterology, Massachusetts General Hospital, Boston, MA (ATC); and Applied Cancer Research-Institution for Translational Research Vienna, Vienna, Austria (ESS).
authors.forename: Kentaro
authors.initials: K
authors.lastname: Inamura
authors.affiliation: From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, MY, KM, YS, SAK, KI, CSF, and SO); the Departments of Nutrition (RN, KW, and ELG), Epidemiology (MW, ELG, SO, and ESS), and Biostatistics (MW), Harvard School of Public Health, Boston, MA; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (MW, XZ, KW, ELG, ATC, CSF, and ESS); the Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan (YB); the Division of Gastroenterology, Massachusetts General Hospital, Boston, MA (ATC); and Applied Cancer Research-Institution for Translational Research Vienna, Vienna, Austria (ESS).
authors.forename: Xuehong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, MY, KM, YS, SAK, KI, CSF, and SO); the Departments of Nutrition (RN, KW, and ELG), Epidemiology (MW, ELG, SO, and ESS), and Biostatistics (MW), Harvard School of Public Health, Boston, MA; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (MW, XZ, KW, ELG, ATC, CSF, and ESS); the Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan (YB); the Division of Gastroenterology, Massachusetts General Hospital, Boston, MA (ATC); and Applied Cancer Research-Institution for Translational Research Vienna, Vienna, Austria (ESS).
authors.forename: Kana
authors.initials: K
authors.lastname: Wu
authors.affiliation: From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, MY, KM, YS, SAK, KI, CSF, and SO); the Departments of Nutrition (RN, KW, and ELG), Epidemiology (MW, ELG, SO, and ESS), and Biostatistics (MW), Harvard School of Public Health, Boston, MA; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (MW, XZ, KW, ELG, ATC, CSF, and ESS); the Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan (YB); the Division of Gastroenterology, Massachusetts General Hospital, Boston, MA (ATC); and Applied Cancer Research-Institution for Translational Research Vienna, Vienna, Austria (ESS).
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.affiliation: From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, MY, KM, YS, SAK, KI, CSF, and SO); the Departments of Nutrition (RN, KW, and ELG), Epidemiology (MW, ELG, SO, and ESS), and Biostatistics (MW), Harvard School of Public Health, Boston, MA; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (MW, XZ, KW, ELG, ATC, CSF, and ESS); the Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan (YB); the Division of Gastroenterology, Massachusetts General Hospital, Boston, MA (ATC); and Applied Cancer Research-Institution for Translational Research Vienna, Vienna, Austria (ESS).
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.affiliation: From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, MY, KM, YS, SAK, KI, CSF, and SO); the Departments of Nutrition (RN, KW, and ELG), Epidemiology (MW, ELG, SO, and ESS), and Biostatistics (MW), Harvard School of Public Health, Boston, MA; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (MW, XZ, KW, ELG, ATC, CSF, and ESS); the Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan (YB); the Division of Gastroenterology, Massachusetts General Hospital, Boston, MA (ATC); and Applied Cancer Research-Institution for Translational Research Vienna, Vienna, Austria (ESS).
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, MY, KM, YS, SAK, KI, CSF, and SO); the Departments of Nutrition (RN, KW, and ELG), Epidemiology (MW, ELG, SO, and ESS), and Biostatistics (MW), Harvard School of Public Health, Boston, MA; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (MW, XZ, KW, ELG, ATC, CSF, and ESS); the Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan (YB); the Division of Gastroenterology, Massachusetts General Hospital, Boston, MA (ATC); and Applied Cancer Research-Institution for Translational Research Vienna, Vienna, Austria (ESS).
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.affiliation: From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, MY, KM, YS, SAK, KI, CSF, and SO); the Departments of Nutrition (RN, KW, and ELG), Epidemiology (MW, ELG, SO, and ESS), and Biostatistics (MW), Harvard School of Public Health, Boston, MA; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (MW, XZ, KW, ELG, ATC, CSF, and ESS); the Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan (YB); the Division of Gastroenterology, Massachusetts General Hospital, Boston, MA (ATC); and Applied Cancer Research-Institution for Translational Research Vienna, Vienna, Austria (ESS).
authors.forename: Eva S
authors.initials: ES
authors.lastname: Schernhammer
mesh_terms: D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000453:epidemiology* / Q000209:etiology; D019175:DNA Methylation; D002149:Energy Intake; D044127:Epigenesis, Genetic; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000008:administration & dosage; D008875:Middle Aged; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D014805:Vitamin B 12 / Q000008:administration & dosage; D025101:Vitamin B 6 / Q000008:administration & dosage
chemical_list: C035170:IGF2 protein, human; D000431:Ethanol; D007335:Insulin-Like Growth Factor II; D025101:Vitamin B 6; D005492:Folic Acid; D008715:Methionine; D014805:Vitamin B 12
keywords: biomarker; epigenetics; imprinting; molecular pathological epidemiology; one carbon metabolism