Carcinogenesis Advance Access originally published online on March 19, 2007
Carcinogenesis 2007 28(7):1504-1509; 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, New York, NY 10029, USA
2 Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA
3 Department of Pediatrics, Mount Sinai School of Medicine, New York, NY 10029, USA
4 Department of Oncological Science, Mount Sinai School of Medicine, New York, NY 10029, USA
5 Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA
6 Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06520, USA
7 Department of Epidemiology, Columbia University, New York, NY 10032, USA
8 Department of Medicine, Columbia University, New York, NY 10032, USA
9 Department of Environmental Health Sciences, Columbia University, New York, NY 10032, USA
* To whom correspondence for reprints should be addressed. Tel: +1 212 241 7519; Fax: +1 212 360 6965; Email: jia.chen{at}mssm.edu
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.
Abbreviations: BHMT, betaine-homocysteine methyltransferase; cSHMT, cytosolic serine hydroxymethyltransferase; DHFR, dihydrafolate reductase; LIBCSP, Long Island Breast Cancer Study Project; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; MTRR, methionine synthase reductase; OR, odds ratio; RFC1, reduced folate carrier 1; TYMS, thymidylate synthase; UTR, untranslated region
Received January 25, 2007; revised March 9, 2007; accepted March 10, 2007.
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