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Candidate pathway polymorphisms in one-carbon metabolism and risk of rectal tumor mutations.

ABSTRACT: We examined candidate polymorphisms in genes involved in the folate-mediated, one-carbon metabolism pathway, DNMT1 1311V, MTHFD1 R134K and R653Q, MTHFR R594Q, MTR D919G, MTRR H595Y and I22M, SHMT1 L474F, SLC19A1 H27R, and TDG G199S, and associations with rectal tumor characteristics. We hypothesized that these candidate genes would influence CpG Island Methylator Phenotype and potentially KRAS2 or TP53 tumors. Data from a population-based study of 747 rectal cases (593 with tumor markers) and 956 controls were evaluated using generalized estimating equations. We observed an increased risk of TP53 tumor mutations in homozygous carriers of the MTHFD1 134K allele (0R=2.0, 95%CI 1.2-3.1, P- trend=0.02). In the presence of low folate intake, the R134K variant was associated with increased risk of CIMP+ tumors (OR=2.8, 95%CI 1.04-7.7). The MTRR I22M variant genotype was associated with a modest increased risk of TP53 mutations (OR=1.7, 95%CI 1.2-2.5, P-trend=0.001). Our findings offer limited support that polymorphisms in one-carbon metabolism genes influence rectal tumor phenotype, and that folate may interact with MTHFD1 to alter CIMP+ risk.

SUBMITTER: Curtin K

PROVIDER: S-EPMC3077233 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Candidate pathway polymorphisms in one-carbon metabolism and risk of rectal tumor mutations.

Curtin Karen K Ulrich Cornelia M CM Samowitz Wade S WS Wolff Roger K RK Duggan David J DJ Makar Karen W KW Caan Bette J BJ Slattery Martha L ML

International journal of molecular epidemiology and genetics 20101105 1

We examined candidate polymorphisms in genes involved in the folate-mediated, one-carbon metabolism pathway, DNMT1 1311V, MTHFD1 R134K and R653Q, MTHFR R594Q, MTR D919G, MTRR H595Y and I22M, SHMT1 L474F, SLC19A1 H27R, and TDG G199S, and associations with rectal tumor characteristics. We hypothesized that these candidate genes would influence CpG Island Methylator Phenotype and potentially KRAS2 or TP53 tumors. Data from a population-based study of 747 rectal cases (593 with tumor markers) and 95 ...[more]

PMID: 21537397

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Project description:Aberrations in one-carbon metabolism were reported to increase breast cancer risk by influencing the DNA synthesis and methylation of DNA and catecholamines. However, the results of these association studies remain inconclusive. We have explored the contribution of eight genetic polymorphisms in modulating the susceptibility to breast cancer by performing a meta-analysis of worldwide studies. In total, 62 case-control studies representing 17 different populations involving 18,117 breast cancer cases and 23,573 healthy controls were included in this meta-analysis. Out of the eight polymorphisms analyzed, methylenetetrahydrofolate reductase (MTHFR) C677T exhibited positive association with the breast cancer risk in both fixed effects (OR 1.14, 95 % CI 1.10-1.17) and random effects (OR 1.10, 95 % CI 1.02-1.18) models. Solute carrier family 19 (folate transporter), member 1 (SLC19A1) G80A exhibited positive association (OR 1.16, 95 % CI 1.03-1.31) while MTR A2756G exhibited an inverse association (OR 0.78, 95 % CI 0.75-0.82) with the breast in fixed effect model alone. Significant heterogeneity was observed in the association of MTHFR C677T with breast cancer even between studies from the same geographical area, specifically among Chinese, Indians, and Turks. Subgroup analysis revealed MTHFR C677T-mediated breast cancer risk in post-menopausal women and women with low dietary intake of folate. Geographical area wise segregation of data revealed MTHFR-mediated increased breast cancer risk in populations who consume methionine-rich diet. Altitude-level variations were observed in the association of SHMT1 C1420T with breast cancer. India and Brazil of same altitude showed an inverse association with this polymorphism, while USA and China that share similar altitude showed a null association. MTHFR C677T and SLC19A1 G80A are the two polymorphisms of one-carbon metabolic pathway that increase breast cancer in the worldwide population. Dietary patterns and altitudinal variations are the likely risk modulators that are contributing toward ethnic- and population-level variations in genetic associations.

Dataset Information

Candidate pathway polymorphisms in one-carbon metabolism and risk of rectal tumor mutations.

Publications

Candidate pathway polymorphisms in one-carbon metabolism and risk of rectal tumor mutations.

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