Carcinogenesis Advance Access published online on March 19, 2007
Carcinogenesis, doi:10.1093/carcin/bgm061
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Polymorphisms of One-carbon Metabolizing Genes and Risk of Breast Cancer in a Population-based Study
1 Department of Community and Preventive Medicine, Mount Sinai School of Medicine
2 Department of Microbiology, Mount Sinai School of Medicine
7 Department of Pediatrics, Mount Sinai School of Medicine
8 Department of Oncological Science, Mount Sinai School of Medicine
3 Department of Epidemiology, University of North Carolina
4 Department of Epidemiology and Public Health, Yale University School of Medicine
5 Department of Epidemiology, Medicine, Columbia University
6 Department of Environmental Health Sciences, Columbia University
Corresponding to [J.C.] and to whom requests for reprints should be addressed at Department of Community and Preventive Medicine, Box 1043, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029. Phone: 212-241-7519; Fax: 212-360-6965; E-mail: jia.chen{at}mssm.edu
One-carbon metabolism facilitates the cross-talk 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 7 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'-UTR (p, trend = 0.07), polymorphisms in the other 6 genes did not substantially modify the risk of breast cancer, nor 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.
Key Words: one-carbon • polymorphism • folate • breast cancer • RTREE
Received January 25, 2007; revised March 9, 2007; accepted March 10, 2007.
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