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A candidate gene study of folate-associated one carbon metabolism genes and colorectal cancer risk.

ABSTRACT: Folate-associated one-carbon metabolism (FOCM) may play an important role in colorectal carcinogenesis. Variation in FOCM genes may explain some of the underlying risk of colorectal cancer.This study utilized data from 1,805 population-based colorectal cancer cases and 2,878 matched sibling controls from the Colon Cancer Family Registry. We used a comprehensive haplotype tagging single nucleotide polymorphism (tagSNP) approach to select 395 tagSNPs in 15 genes involved in folate and vitamin B(12) metabolism. Genotyping was done using the Illumina GoldenGate or Sequenom platforms. Risk factor and dietary data were collected using self-completed questionnaires. Microsatellite instability (MSI) status was determined using standard techniques, and tumor subsite was obtained from pathology reports. The association between SNPs and colorectal cancer was assessed using conditional logistic regression with sibships as the matching factor and assuming a log additive or codominant model.In the log additive model, two linked (r(2) = 0.99) tagSNPs in the DHFR gene (rs1677693 and rs1643659) were associated with a significant decrease in colorectal cancer risk after correction for multiple testing (odds ratio, 0.87; 95% confidence interval, 0.71-0.94; P = 0.029; and odds ratio, 0.87; 95% confidence interval, 0.71-0.95; P = 0.034 for rs1677693 and rs1643659, respectively). These two linked (r(2) = 0.99) tagSNPs and one tagSNP in the MTR gene (rs4659744) were significantly associated with reduced colorectal cancer risk only among individuals not using multivitamin supplements.Overall, we found only moderate evidence that genetic variation in 15 folate pathway genes may affect colorectal cancer risk except in non-multivitamin users.This study suggests that multivitamin supplement use may modify the association between folate pathway genes and colorectal cancer risk in a post-folic-acid-supplemented population.

SUBMITTER: Levine AJ

PROVIDER: S-EPMC2950115 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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A candidate gene study of folate-associated one carbon metabolism genes and colorectal cancer risk.

Levine A Joan AJ Figueiredo Jane C JC Lee Won W Conti David V DV Kennedy Kathleen K Duggan David J DJ Poynter Jenny N JN Campbell Peter T PT Newcomb Polly P Martinez Maria Elena ME Hopper John L JL Le Marchand Loic L Baron John A JA Limburg Paul J PJ Ulrich Cornelia M CM Haile Robert W RW

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20100701 7

<h4>Background</h4>Folate-associated one-carbon metabolism (FOCM) may play an important role in colorectal carcinogenesis. Variation in FOCM genes may explain some of the underlying risk of colorectal cancer.<h4>Methods</h4>This study utilized data from 1,805 population-based colorectal cancer cases and 2,878 matched sibling controls from the Colon Cancer Family Registry. We used a comprehensive haplotype tagging single nucleotide polymorphism (tagSNP) approach to select 395 tagSNPs in 15 genes ...[more]

PMID: 20615890

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Project description:Investigations of folate-mediated one-carbon metabolism (FOCM) genes and gene-nutrient interactions with respect to colorectal cancer (CRC) risk are limited to candidate polymorphisms and dietary folate. This study comprehensively investigated associations between genetic variants in FOCM and CRC risk and whether the FOCM nutrient status modified these associations.Two hundred eighty-eight candidate and tagging single-nucleotide polymorphisms (SNPs) in 30 FOCM genes were genotyped for 821 incident CRC case-control matched pairs in the Women's Health Initiative Observational Study cohort. FOCM biomarkers (red blood cell [RBC] folate, plasma folate, pyridoxal-5'-phosphate [PLP], vitamin B12, and homocysteine) and self-reported alcohol consumption were measured at the baseline. Conditional logistic regression was implemented; effect modification was examined on the basis of known enzyme-nutrient relations.Statistically significant associations were observed between CRC risk and functionally defined candidate SNPs of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1; K134R), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR; P450R), and PR domain containing 2 with ZNF domain (PRDM2; S450N) and a literature candidate SNP of thymidylate synthase (TYMS; g.676789A>T; nominal P?<?.05). In addition, suggestive associations were noted for tagging SNPs in cystathionine-?-synthase (CBS), dihydrofolate reductase (DHFR), DNA (cytosine-5-)-methyltransferase 3? (DNMT3B), methionine adenosyltransferase I ? (MAT1A), MTHFD1, and MTRR (nominal P?<?.05; adjusted P, not significant). Significant interactions between nutrient biomarkers and candidate polymorphisms were observed for 1) plasma/RBC folate and folate hydrolase 1 (FOLH1), paraoxonase 1 (PON1), transcobalamin II (TCN2), DNMT1, and DNMT3B; 2) plasma PLP and TYMS TS3; 3) plasma B12 and betaine-homocysteine S-methyltransferase 2 (BHMT2); and 4) homocysteine and methylenetetrahydrofolate reductase (MTHFR) and alanyl-transfer RNA synthetase (AARS).Genetic variants in FOCM genes are associated with CRC risk among postmenopausal women. FOCM nutrients continue to emerge as effect modifiers of genetic influences on CRC risk.

Dataset Information

A candidate gene study of folate-associated one carbon metabolism genes and colorectal cancer risk.

Publications

A candidate gene study of folate-associated one carbon metabolism genes and colorectal cancer risk.

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