title: Polymorphisms in the reduced folate carrier, thymidylate synthase, or methionine synthase and risk of colon cancer.
abstract: Folate metabolism supports the synthesis of nucleotides as well as the transfer of methyl groups. Polymorphisms in folate-metabolizing enzymes have been shown to affect risk of colorectal neoplasia and other malignancies. Using data from a population-based incident case-control study (1,600 cases and 1,962 controls), we investigated associations between genetic variants in the reduced folate carrier (RFC), thymidylate synthase (TS), methionine synthase (MTR), and 5,10-methylenetetrahydrofolate reductase (MTHFR) and colon cancer risk. The TS enhancer region (TSER) variant was associated with a reduced risk among men [2rpt/2rpt versus 3rpt/3rpt wild-type; odds ratio (OR), 0.7; 95% confidence interval, 0.6-0.98] but not women. When combined genotypes for both TS polymorphisms (TSER and 3'-untranslated region 1494delTTAAAG) were evaluated, ORs for variant genotypes were generally below 1.0, with statistically significantly reduced risks among women. Neither MTR D919G nor RFC 80G>A polymorphisms were associated with altered colon cancer risk. Because folate metabolism is characterized by interrelated reactions, we evaluated gene-gene interactions. Genotypes resulting in reduced MTHFR activity in conjunction with low TS expression were associated with a reduced risk of colon cancer. When dietary intakes were taken into account, individuals with at least one variant TSER allele (3rpt/2rpt or 2rpt/2rpt) were at reduced risk in the presence of a low folate intake. This study supports findings from adenoma studies indicating that purine synthesis may be a relevant biological mechanism linking folate metabolism to colon cancer risk. A pathway-based approach to data analysis is needed to help discern the independent and combined effects of dietary intakes and genetic variability in folate metabolism.
authors.affiliation: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M4-B402 Seattle, WA 98109-1024, USA. nulrich@fhcrc.org
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
authors.forename: Karen
authors.initials: K
authors.lastname: Curtin
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.forename: Jeannette
authors.initials: J
authors.lastname: Bigler
authors.forename: Bette
authors.initials: B
authors.lastname: Caan
authors.forename: Martha L
authors.initials: ML
authors.lastname: Slattery
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D000236:Adenoma / Q000209:etiology / Q000235:genetics; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003110:Colonic Neoplasms / Q000209:etiology / Q000235:genetics*; D004032:Diet; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D058978:Reduced Folate Carrier Protein; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism
chemical_list: D026901:Membrane Transport Proteins; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D005492:Folic Acid; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D013940:Thymidylate Synthase