Reiko Nishihara1, Molin Wang1, Zhi Rong Qian1, Yoshifumi Baba1, Mai Yamauchi1, Kosuke Mima1, Yasutaka Sukawa1, Sun A Kim1, Kentaro Inamura1, Xuehong Zhang1, Kana Wu1, Edward L Giovannucci1, Andrew T Chan1, Charles S Fuchs1, Shuji Ogino1, Eva S Schernhammer1. 1. 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).
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. DESIGN: 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.
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. DESIGN: 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.
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