Abstract
Objective. Methylenetetrahydrofolate reductase (MTHFR), a polymorphic enzyme involved in folate metabolism, plays a role in DNA biosynthesis, methylation, and repair in actively dividing cells. Because breast-cell division occurs in women with active ovulatory cycles, polymorphisms in the MTHFR gene could be a risk factor for breast cancer.
Methods. We genotyped 352 clinic-based study subjects for MTHFR, 105 subjects with breast cancer and 247 with benign breast disease, histopathologically classified as high-risk or low-risk for breast cancer. Questionnaire data were collected prior to biopsy to blind subjects and interviewers to diagnoses.
Results. Premenopausal women with the MTHFR polymorphism had a threefold increased breast cancer risk (OR = 2.8; 95%CI: 1.02–7.51) compared to the clinic-based controls with benign breast disease. Results were similar using either low- or high-risk controls. However, risk for postmenopausal women was not elevated (OR = 0.8; 95%CI 0.4–1.4). No significant interaction between genotype and smoking or alcohol was found, but polymorphic MTHFR decreased the likelihood of drinking alcohol (OR = 0.5; 95%CI 0.3–0.9).
Conclusion. These data suggest that polymorphic MTHFR increases risk of premenopausal, but not postmenopausal, breast cancer. These findings should be explored with a larger sample size in order to analyze gene–environment interactions between MTHFR and folate. Once the intricate relationship between diet and breast cancer has been elucidated, new cancer control initiatives can be considered such as folate chemoprevention trials in high-risk individuals.
Similar content being viewed by others
References
Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61: 759-767, 1990
Greenblatt MS, Bennett WP, Hollstein M, Harris CC: Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54: 4855-4878, 1994
Nass SJ, Herman JG, Gabrielson E: Aberrant methylation of the estrogen receptor and E-cadherin 5′' CpG islands increases with malignant progression in human breast cancer. Cancer Res 60: 4346-4348, 2000
Frosst P, Blom HJ, Milos R: A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10: 111-113, 1995
Delfino RJ, Sinha R, Smith C: Breast cancer, heterocyclic aromatic amines from meat and N-acetyltransferase 2 genotype. Carcinogenesis 21: 607-615, 2000
Botto LD, Yang: 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol 151: 862-877, 2000
Dupont WD, Parl FF, Hartmann WH: Breast cancer risk associated with proliferative breast disease and atypical hyperplasia. Cancer 71: 1258-1265, 1993
Chen J, Giovannucci E, Kelsey K: A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res 56: 4862-4864, 1996
Kang SS, Wong PW, Susmano A, Sora J, Norusis M, Ruggie N: Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet 48: 536-545, 1991
Henderson BE, Ross R, Bernstein L: Estrogens as a cause of human cancer: the Richard and Hinda Rosenthal Foundation award lecture. Cancer Res 48: 246-253, 1988
Semenza JC, Ziogas A, Largent J, Peel D, Anton-Culver H: Gene-environment interactions in renal cell carcinoma. Am J Epidemiol 153: 851-859, 2001
Slattery ML, Potter JD, Samowitz W, Schaffer D, Leppert M: Methylenetetra-hydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 8: 513-518, 1999
Ma J, Stampfer MJ, Giovannucci E: Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res 57: 1098-1102, 1997
Chen J, Giovannucci E, Kelsey K: A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res 56: 4862-4864, 1996
Potter JD: Colorectal cancer: molecules and populations. J Natl Cancer Inst 91: 916-932, 1999
Skibola CF, Smith MT, Kane E: Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci USA 96: 12810-12815, 1999
Viel A, Dall'Agnese L, Simone F: Loss of heterozygosity at the 5,10-methylenetetrahydrofolate reductase locus in human ovarian carcinomas. Br J Cancer 75: 1105-1110, 1997
Esteller M, Garcia A, Martinez-Palones JM, Xercavins J, Reventos J: Germ line polymorphisms in cytochrome-P450 1A1 and methylenetetrahydrofolate reductase (C4887 CYP1A1) (MTHFR) genes and endometrial cancer susceptibility. Carcinogenesis 18: 2307-2311, 1997
Gershoni-Baruch R, Dagan E, Israeli D, Kasinetz L, Kadouri E, Friedman E: Association of the C677T polymorphism in the MTHFR gene with breast and/or ovarian cancer risk in Jewish women. Eur J Cancer 36: 2313-2316, 2000
Longnecker MP, Berlin JA, Orza MJ, Chalmers TC: A meta-analysis of alcohol consumption in relation to risk of breast cancer. JAMA 260: 652-656, 1988
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Semenza, J.C., Delfino, R.J., Ziogas, A. et al. Breast Cancer Risk and Methylenetetrahydrofolate Reductase Polymorphism. Breast Cancer Res Treat 77, 217–223 (2003). https://doi.org/10.1023/A:1021843019755
Issue Date:
DOI: https://doi.org/10.1023/A:1021843019755