Polymorphisms of one-carbon metabolizing genes and risk of breast cancer in a population-based study Free

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One-carbon metabolism facilitates the cross-talk between genetic and epigenetic processes by playing critical roles in both DNA methylation and DNA synthesis. Its critical role in carcinogenesis makes it a good candidate to study the risk of breast cancer. We previous reported that a functional polymorphism in the key one-carbon-metabolizing gene, i.e. MTHFR 677C>T, was associated with breast cancer risk in the population-based Long Island Breast Cancer Study Project. For the present study, we systematically investigated the relationship of breast cancer risk and putatively functional polymorphisms of 7 other one-carbon metabolic genes, i.e. TYMS, DHFR, MTR, MTRR, BHMT, cSHMT and RFC1, in the same population. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by using logistic regression. Overall, polymorphisms in these 7 genes were not independently associated with breast cancer risk, nor did they modify the risk associated with dietary intakes of folate and related B vitamins. However, we observed a significant multiplicative interaction (p=0.04) between MTHFR C677T and a tandem repeat polymorphism in the TYMS promoter. As an attempt to tease out important or rate-limiting genes in the intricately related one-carbon pathway, a recursive partitioning method, RTREE, was used to build binary classification trees. RTREE results indicate MTHFR is the rate-limiting enzyme in the pathway, consistent with our epidemiological findings. Our findings underscore the importance of one-carbon metabolism in breast cancer etiology. Although the pathway is a network of interrelated enzymes, redundancy exists; evaluating the rate-limiting enzyme and its interaction with both environment and other genes is critical in assessing breast cancer risk.