5-10-methylenetetrahydrofolic-acid and Adenoma

Dietary folate status appears to influence risk for colorectal cancer possibly by alterations in DNA methylation and nucleotide precursor pools. Polymorphisms (677C-->T and 1298A-->C) in methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, determines enzyme activity. The frequency of polymorphisms in the gene varies extensively in different populations. We sought to determine the association between folate status, folate metabolism, DNA methylation, tobacco, alcohol consumption, and the risk of colorectal adenomas in African Americans. Among 58 patients who underwent a clinically indicated colonoscopy, 23 patients with histology confirmed colorectal polyps and 35 patients without were recruited for a case-control study. Blood samples were collected from fasting patients for determination of serum and red blood cell (RBC) folate, homocysteine, vitamin B(12), and methylation status. Polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) technique was performed to identify the MTHFR 677 C-->T polymorphism and specific PCR was used to analyze adenomatous polyposis coli (APC) gene-promoter sequence methylation. Among 23 cases, 49 polyps (adenomatous, n = 41 and hyperplastic, n= 8) were identified. Twenty-eight (57%) of the polyps were on the left side and 21 (42%) were on the right side of the colon. There was no association between the presence of colon polyps and levels of folate (serum, RBC), vitamin B(12), or homocysteine. Forty-eight individuals (84%) were homozygous for 677 CC. Of these individuals, 18 (37.5%) had >/=1 colorectal polyps, whereas 30 (62.5%) had no polyps. Nine individuals were heterozygous for 677 CT, and 4 (44%) of these individuals had colon polyps. Eighty-eight percent of the APC gene-promoter sequences tested using peripheral blood DNA from patients were unmethylated. Among the individuals who showed APC methylation, 66% had polyps; 33% were polyp free using their blood DNA. There was highly significant association between smoking and alcohol consumption with the presence of a colon polyp (P= .0006 and P= .05, respectively). In conclusion, the lack of the 677 TT may be a significant risk factor for colon neoplasm in the African-American population. Smoking and alcohol consumption were found to be risk factors for colon polyps. APC gene-promoter sequence methylation found in peripheral blood may be an indicator of risk for polyp formation and an important screening tool.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Alcohol Drinking; Black or African American; Case-Control Studies; Colonic Polyps; Colorectal Neoplasms; DNA Methylation; Female; Folic Acid; Genes, APC; Homocysteine; Humans; Male; Middle Aged; Promoter Regions, Genetic; Smoking; Tetrahydrofolates; Vitamin B 12; Vitamins

Aberrant DNA methylation occurs in a subset of colorectal cancers and is characterized by regional areas of hypermethylation at CpG islands. The aims of this study were firstly to evaluate the levels of folate intermediates (FIs) in tumors with aberrant DNA methylation and secondly to determine whether these levels are affected by polymorphisms in key genes involved in folate metabolism.. The concentrations of two major intracellular FIs, 5,10-methylenetetrahydrofolate and tetrahydrofolate (FH4), were measured in 103 surgically resected colorectal cancers. DNA hypermethylation at seven different CpG islands was measured using the MethylLight assay. Genotyping for polymorphisms in the thymidylate synthase, cystathionine beta-synthase, methionine synthase, and methylenetetrahydrofolate reductase (MTHFR) genes was carried out using PCR and PCR-RFLP.. Significantly higher levels of FH4 were found in tumors from the proximal colon compared with those originating in the distal colon and rectum. Tumors with aberrant DNA methylation of CpG islands within promoter regions of the hMLH1, TIMP3, and ARF genes also contained higher levels of both 5,10-methylenetetrahydrofolate and FH4. In contrast, patients who were homozygous for the C667T polymorphism of the MTHFR gene had significantly lower concentrations of both these FIs in their tumor tissue.. The concentrations of FIs in colorectal tumors are directly related to the presence of frequent DNA hypermethylation and inversely related to the presence of a common polymorphism in the MTHFR gene. FIs could serve as biochemical markers for the risk of developing this disease, as well as for the prediction of toxicity and efficacy of fluorouracil-based treatments.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Adenocarcinoma; Adenoma; Aged; Colorectal Neoplasms; CpG Islands; Cystathionine beta-Synthase; DNA Methylation; Female; Genotype; Humans; Male; Methylenetetrahydrofolate Reductase (NADPH2); Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Tetrahydrofolates; Thymidylate Synthase