Polymorphisms of one-carbon-metabolizing genes and risk of breast cancer in a population-based study.
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.
Xu
Xinran
X
Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Gammon
Marilie D
MD
Zhang
Heping
H
Wetmur
James G
JG
Rao
Manlong
M
Teitelbaum
Susan L
SL
Britton
Julie A
JA
Neugut
Alfred I
AI
Santella
Regina M
RM
Chen
Jia
J
D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D009518:New York; D019875:One-Carbon Group Transferases / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D012306:Risk; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism; D014803:Vitamin B Complex / Q000008:administration & dosage
D014803:Vitamin B Complex; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D019875:One-Carbon Group Transferases; D013940:Thymidylate Synthase