Alcohol, one-carbon nutrient intake, and risk of colorectal cancer according to tumor methylation level of IGF2 differentially methylated region
American Journal of Clinical Nutrition
Biomarker; Epigenetics; Imprinting; Molecular pathological epidemiology; One carbon metabolism
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 insulinlike 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. © 2014 American Society for Nutrition.
Nishihara, R., Wang, M., Qian, Z., Baba, Y., Yamauchi, M., Mima, K., Sukawa, Y., Kim, S., Inamura, K., Zhang, X., Wu, K., Giovannucci, E., Chan, A., Fuchs, C., Ogino, S., & Schernhammer, E. (2014). Alcohol, one-carbon nutrient intake, and risk of colorectal cancer according to tumor methylation level of IGF2 differentially methylated region. American Journal of Clinical Nutrition, 100 (6). http://dx.doi.org/10.3945/ajcn.114.095539