DNA Methyltransferase and Alcohol Dehydrogenase: Gene-Nutrient Interactions in Relation to Risk of Colorectal Polyps

Abstract

Disturbances in DNA methylation are a characteristic of colorectal carcinogenesis. Folate-mediated one-carbon metabolism is essential for providing one-carbon groups for DNA methylation via DNA methyltransferases (DNMTs). Alcohol, a folate antagonist, could adversely affect one-carbon metabolism. In a casecontrol study of colorectal polyps, we evaluated three single nucleotide polymorphisms (À149C>T, À283T>C, À579G>T) in the promoter region of the DNMT3b gene, and a functional polymorphism in the coding region of the alcohol dehydrogenase ADH1C gene, ADH1C *2. Cases had a first diagnosis of colorectal adenomatous (n = 530) or hyperplastic (n = 202) polyps at the time of colonoscopy, whereas controls were polyp-free (n = 649). Multivariate logistic regression analysis was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI). There were no significant main associations between the DNMT3b or ADH1C polymorphisms and polyp risk. However, DNMT3b À149TT was associated with an increase in adenoma risk among individuals with low folate and methionine intake (OR, 2.00; 95% CI, 1.06-3.78, P interaction = 0.10). The ADH1C *2/*2 genotype was associated with a possibly elevated risk for adenomatous polyps among individuals who consumed >26 g of alcohol/d (OR, 1.95; 95% CI, 0.60-6.30), whereas individuals who were wildtype for ADH1C were not at increased risk of adenoma (P interaction = 0.01). These gene-diet interactions suggest that polymorphisms relevant to DNA methylation or alcohol metabolism may play a role in colorectal carcinogenesis in conjunction with a high-risk diet.

Genetic Variants of Methyl Metabolizing Enzymes and Epigenetic Regulators: Associations with Promoter CpG Island Hypermethylation in Colorectal Cancer

“…However, an increased risk for colorectal cancer could be expected because this polymorphism increases enzymatic activity of DNMT3b (21), and DNMT3b overexpression was associated with increased promoter hypermethylation in different types of cancers (15-17, 19, 20). Moreover, positive associations were observed with colorectal polyps and early onset of colorectal cancer in hereditary nonpolyposis colorectal cancer patients (23,25) and several other cancers (21,22,24). Other genetic variants of DNMT3b that have been identified are the -283T→C and -579G→T polymorphisms, of which the latter was associated with reduced colorectal cancer risk (67).…”

“…Interestingly, enzymatic activity of DNMT3b was decreased when the rare allele of -283T→C was present (68). Apparently, different polymorphisms in DNMT3b may have opposite effects and individuals may be more susceptible to carcinogenesis with higher DNMT3b enzymatic activity (21)(22)(23)25), whereas decreased activity may protect against carcinogenesis (67,68). Whereas a similar but weak inverse association was previously observed with breast cancer for the DNMT3b C→T (rs406193) polymorphism (30), we observed an inverse association with colorectal cancer among women.…”

“…Several single-nucleotide polymorphisms of the DNMT3b gene have been identified, which may affect catalytic activity of the DNMT3b enzyme. For example, the rare T allele of the DNMT3b C→T (rs2424913) polymorphism was found to significantly increase DNTM3b promoter activity and was associated with an increased risk for lung cancer (21), prostate cancer (22), and colorectal polyps, including colorectal adenomas (23), or with prognosis of head and neck cancer (24). Moreover, subjects with hereditary nonpolyposis colorectal cancer carrying the TT genotype developed colorectal cancer at a younger age compared with those homozygous for the wild-type DNMT3b CC allele (25).…”

Investigation of the Prevalence and Number of Aberrant Crypt Foci Associated with Human Colorectal Neoplasm

“…Tobacco contains a large number of carcinogens that may bind to DNA and form adducts, potentially causing irreversible genetic damage to the normal colonic mucosa (31). On the other hand, alcohol is metabolized to acetaldehyde, which binds to DNA and forms carcinogenic adducts (32). Therefore, these 2 factors may share a common pathway in promoting colorectal carcinogenesis at an early stage and initiating ACF formation.…”

Lifestyle Risk Factors for Serrated Colorectal Polyps: A Systematic Review and Meta-analysis

“…Several studies have investigated SP risk in relation to genetic variants linked to the metabolism of the risk factors outlined such as alcohol 87 , smoking 88 ,body fatness 81 and diet 28,54,64 . However, only one study has investigated known CRC mutations -APC, KRAS and MSI interactions with lifestyle factors (namely, smoking status) and SP risk, and found that such mutations were only present in HP patients who smoked, and were not seen in non-smokers 41 .…”