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 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-β2 in breast cancer; in addition, we evaluated case-case comparisons of 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 (OR) and 95% confidence intervals (CI). 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, ER 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-β2 genes in breast cancer.

The influence of one-carbon metabolism on gene promoter methylation in a population-based breast cancer study

“…Another recent study examined promoter methylation of three genes (E-cadherin, p16 and RARβ2) among ~800 breast tumors and found no evidence that MTHFR C677T, A1298C and MTR A2756G polymorphisms were associated methylation status. 32 We did not observe significant association for these three polymorphisms in our study, either.…”

Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues

“…51 In addition, MTR affects the availability of tetrahydrofolate for nucleotide biosynthesis. 51 In one of our earlier analyses in a breast cancer case-control study, 31 we observed no significant association between MTR A2756G and hypermethylation in select gene promoters (measured in breast tumor tissues), including E-cadherin, p16 INK4a , and RAR-b2. We 52 and others 53 have similarly found no association between variation in this SNP and percent methylation in the promoter regions of some specific genes, in histologically normal breast tissues or in breast tumor tissues.…”

“…28 There have been reports of an association between single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in onecarbon metabolism and gene-specific promoter methylation levels in some human cancers, 29,30 although findings for breast cancer have been inconclusive. 29,31 Little is known about the association between variation in one-carbon metabolism genes and genome-wide methylation. Further, while there is evidence that dietary folate intake may be associated with genome-wide methylation in WBCs, [32][33][34] it remains to be elucidated whether an association also exists for methylation levels in breast tissues with folate concentrations in the breast.…”

Gene polymorphisms in TYMS, MTHFR, p53 and MDR1 as risk factors for breast cancer: A case-control study

“…There are some studies in favor of this argument (43), most of them in people from Turkey and oriental countries (44,45). This hypothesis is refuted by different authors in different populations (46,47). Moreover, there are studies that support a possible benefit of this polymorphism in the prevention of breast cancer (48).…”