We propose to conduct a prospective study of nutritional biomarkers and corresponding gene variants involved in one-carbon metabolism-and their interactive effects-on breast cancer risk in the Women's Health Study (WHS). A total of 1,100 incident cases of breast cancer will be identified and confirmed among 28,345 participants with archived baseline blood specimens. We will assay five nutritional biomarkers (i.e. plasma folate, vitamins B6 and B12, cysteine, and homocysteine). Applying state-of-the-art genotyping technology and statistical methods, we will evaluate functional variants and determine the structure of haplotypes in twelve relevant candidate genes. These genes will include glutamatecysteine ligase (GCLC [catalytic subunit] and GCLM[regulatory subunit]), folate-metabolizing genes (reduced folate carrier-1 [RFC], 5,10-methylene-tetrahydrofolate reductase [MTHFR], methionine synthase [MTR], methionine synthase reductase [MTRR], serine hydroxymethyltransferase [SHMT1], and thymidylate synthase [TYMS]), catechol-O-methyltransferase (COMT), and DNA repair genes (X-ray repair cross complementing [XRCC]-1, 2, and 3). There are at least three interrelated pathways by which these markers may be associated with breast cancer risk. First, folate and vitamin B12 affect methyl group availability and may thus prevent abnormal DNA methylation. Second, folate and vitamins B6 and B12 influence DNA synthesis and repair. Third, cysteine is the key amino acid in the synthesis of glutathione (GSH), an important intracellular antioxidant and detoxifying agent. GCLC and GCLM genes encode a rate-limiting enzyme for GSH biosynthesis from cysteine. Available data also suggest that folate interacts with alcohol intake to affect breast cancer risk. However, no published data have evaluated whether GCLC, GCLM, RFC, MTR, MTRR, SHMT1, and TYMS polymorphisms affect breast cancer risk. Findings from this study will help provide a basis for public health recommendations regarding optimal levels of folate and B vitamin intakes, suggest new prevention strategies, and identify high-risk individuals. Several unique features of the WHS, including its prospective design, large sample size, long duration, high follow-up rates, availability of stored blood specimens, comprehensive covariate information, and cost efficiency, make this cohort a valuable and exceptional resource for the etiologic investigation of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104871-03
Application #
7250218
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Wang, Wendy
Project Start
2005-09-28
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
3
Fiscal Year
2007
Total Cost
$283,780
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Song, Yiqing; Manson, Joann E; Lee, I-Min et al. (2012) Effect of combined folic acid, vitamin B(6), and vitamin B(12) on colorectal adenoma. J Natl Cancer Inst 104:1562-75
Lin, Jennifer; Lee, I-Min; Song, Yiqing et al. (2010) Plasma homocysteine and cysteine and risk of breast cancer in women. Cancer Res 70:2397-405
Lin, Jennifer; Lee, I-Min; Cook, Nancy R et al. (2008) Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women. Am J Clin Nutr 87:734-43
Lin, Jennifer; Manson, JoAnn E; Selhub, Jacob et al. (2007) Plasma cysteinylglycine levels and breast cancer risk in women. Cancer Res 67:11123-7