title: DNA promoter methylation in breast tumors: no association with genetic polymorphisms in MTHFR and MTR.
abstract: Aberrant promoter methylation is recognized as an important feature of breast carcinogenesis. We hypothesized that genetic variation of genes for methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR), two critical enzymes in the one-carbon metabolism, may alter DNA methylation levels and thus influence DNA methylation in breast cancer. We evaluated case-control association of MTHFR C677T, A1298C, and MTR A2756G polymorphisms for cases strata-defined by promoter methylation status for each of three genes, E-cadherin, p16, and RAR-beta2 in breast cancer; in addition, we evaluated case-case comparisons of the likelihood of promoter methylation in relation to genotypes using a population-based case-control study conducted in Western New York State. Methylation was evaluated with real-time methylation-specific PCRs for 803 paraffin-embedded breast tumor tissues from women with primary, incident breast cancer. We applied unordered polytomous regression and unconditional logistic regression to derive adjusted odds ratios and 95% confidence intervals. We did not find any association of MTHFR and MTR polymorphisms with breast cancer risk stratified by methylation status nor between polymorphisms and likelihood of promoter methylation of any of the genes. There was no evidence of difference within strata defined by menopausal status, estrogen receptor status, folate intake, and lifetime alcohol consumption. Overall, we found no evidence that these common polymorphisms of the MTHFR and MTR genes are associated with promoter methylation of E-cadherin, p16, and RAR-beta2 genes in breast cancer.
authors.affiliation: Department of Social and Preventive Medicine, School of Public Health and Health Professions, 270 Farber Hall, University at Buffalo, Buffalo, NY 14214, USA. mtao@buffalo.edu
authors.forename: Meng Hua
authors.initials: MH
authors.lastname: Tao
authors.forename: Peter G
authors.initials: PG
authors.lastname: Shields
authors.forename: Jing
authors.initials: J
authors.lastname: Nie
authors.forename: Catalin
authors.initials: C
authors.lastname: Marian
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
authors.forename: Susan E
authors.initials: SE
authors.lastname: McCann
authors.forename: Mary
authors.initials: M
authors.lastname: Platek
authors.forename: Shiva S
authors.initials: SS
authors.lastname: Krishnan
authors.forename: Bin
authors.initials: B
authors.lastname: Xie
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Edge
authors.forename: Janet
authors.initials: J
authors.lastname: Winston
authors.forename: Dominica
authors.initials: D
authors.lastname: Vito
authors.forename: Maurizio
authors.initials: M
authors.lastname: Trevisan
authors.forename: Jo L
authors.initials: JL
authors.lastname: Freudenheim
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics*; D000704:Analysis of Variance; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019175:DNA Methylation; D005260:Female; D005838:Genotype; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D011110:Polymorphism, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; C471638:CBLL1 protein, human; D044767:Ubiquitin-Protein Ligases