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Effects of Dietary Folate and Alcohol Intake on Promoter Methylation in Sporadic Colorectal Cancer: The Netherlands Cohort Study on Diet and Cancer¹

The Research Institute GROW, Department of Pathology, University Maastricht, 6200 MD Maastricht, the Netherlands [M. v. E., G. M. J. M. R., A. P. d. B., A. F. P. M. d. G.]; Tumor Biology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231 [M. v. E., S. B. B., J. G. H.]; Research Institute NUTRIM, Department of Epidemiology, University Maastricht, 6200 MD Maastricht, the Netherlands [M. P. W., M. B., P. A. v. d. B.]; and TNO Nutrition and Food Research, 3700 AJ Zeist, the Netherlands [R. A. G.]

Sporadic colorectal cancer (CRC) is characterized by genetic and epigenetic changes such as regional DNA hypermethylation and global DNA hypomethylation. Epidemiological and animal studies suggest that aberrant DNA methylation is associated with low dietary folate intake, which is aggravated by high alcohol intake. The relationship between promoter methylation of genes involved in CRC carcinogenesis and folate and alcohol intake was investigated. Methylation of the APC-1A, p14^ARF, p16^INK4A, hMLH1, O⁶-MGMT, and RASSF1A promoters was studied using methylation-specific PCR in 122 sporadic CRCs, derived from patients with folate and alcohol intake at either the lower or the higher quintiles of the distribution. Overall, promoter hypermethylation frequencies observed were: 39% for APC; 33% for p14^ARF; 31% for p16^INK4A; 29% for hMLH1; 41% for O⁶-MGMT; and 20% for RASSF1A. For each of the tested genes, the prevalence of promoter hypermethylation was higher in CRCs derived from patients with low folate/high alcohol intake (n = 61) when compared with CRCs from patients with high folate/low alcohol intake (n = 61), but the differences were not statistically significant. The number of CRCs with at least one gene methylated was higher (84%) in the low folate intake/high alcohol intake group when compared with the high folate intake/low alcohol intake group (70%; P = 0.085). Despite the size limitations of this study, these data suggest that folate and alcohol intake may be associated with changes in promoter hypermethylation in CRC.

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