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- Title
Polymorphisms of one-carbon-metabolizing genes and risk of breast cancer in a population-based study.
- Authors
Xinran Xu; Marilie D. Gammon; Heping Zhang; James G. Wetmur; Manlong Rao; Susan L. Teitelbaum; Julie A. Britton; Alfred I. Neugut; Regina M. Santella; Jia Chen
- Abstract
One-carbon metabolism facilitates the crosstalk between genetic and epigenetic processes and plays critical roles in both DNA methylation and DNA synthesis, making it a good candidate for studying the risk of breast cancer. We previously reported that polymorphisms in methylenetetrahydrofolate reductase (MTHFR) in one-carbon pathway were associated with breast cancer risk in the population-based Long Island Breast Cancer Study Project. Herein, we systematically investigated putatively functional polymorphisms of seven other one-carbon-metabolizing genes in relation to the breast cancer risk in the same population. Except for a slight indication of increased risk of breast cancer associated with the double repeat (2R) allele in the thymidylate synthase (TYMS) 5′-untranslated region (UTR) (P, trend = 0.07), polymorphisms in the other six genes did not substantially modify the risk of breast cancer, or did they modify the risk associated with dietary intakes of folate and related B vitamins. However, we observed a significant multiplicative interaction between the MTHFR 677C>T and the TYMS 5′-UTR polymorphisms (P = 0.02). We used a recursive partitioning method, RTREE, in an attempt to tease out important or rate-limiting genes encoding these intricately related enzymes. Results from RTREE analyses indicate that MTHFR and TYMS are the two leading rate-limiting enzymes 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 environment and other genes within the same pathway is critical in assessing breast cancer risk.
- Subjects
GENETIC polymorphisms; CARBON; GENES; BREAST cancer risk factors
- Publication
Carcinogenesis, 2007, Vol 28, Issue 7, p1504
- ISSN
0143-3334
- Publication type
Article
- DOI
10.1093/carcin/bgm061