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Breast Cancer Research
Published in: Breast Cancer Research 6/2009

Open Access 01-12-2009 | Research article

MTHFR C677T and postmenopausal breast cancer risk by intakes of one-carbon metabolism nutrients: a nested case-control study

Authors: Sonia S Maruti, Cornelia M Ulrich, Eldon R Jupe, Emily White

Published in: Breast Cancer Research | Issue 6/2009

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Abstract

Introduction

The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene has been hypothesized to increase breast cancer risk. However, results have been inconsistent, and few studies have reported the association by menopausal status or by intakes of nutrients participating in one-carbon metabolism. Our aims were to investigate whether MTHFR C677T was associated with postmenopausal breast cancer risk and whether this relation was modified by intakes of folate, methionine, vitamins B2, B6, and B12, and alcohol.

Methods

We studied 318 incident breast cancer cases and 647 age- and race-matched controls participating in a nested case-control study of postmenopausal women within the VITamins And Lifestyle (VITAL) cohort. Genotyping was conducted for MTHFR C677T and dietary and supplemental intakes were ascertained from a validated questionnaire. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression.

Results

We observed a 62% increased risk of breast cancer among postmenopausal women with the TT genotype (OR = 1.62; 95% CI: 1.05 to 2.48). Women with a higher number of variant T alleles had higher risk of breast cancer (P for trend = 0.04). Evidence of effect-modification by intakes of some B vitamins was observed. The most pronounced MTHFR-breast cancer risks were observed among women with the lowest intakes of dietary folate (P for interaction = 0.02) and total (diet plus supplemental) vitamin B6 (P for interaction = 0.01), with no significant increased risks among women with higher intakes.

Conclusions

This study provides support that the MTHFR 677TT genotype is associated with a moderate increase in risk of postmenopausal breast cancer and that this risk may be attenuated with high intakes of some one-carbon associated nutrients.
Literature
1.
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, Heuvel van den LP, Rozen R: A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genetics. 1995, 10: 111-113. 10.1038/ng0595-111.CrossRefPubMed
2.
Weisberg IS, Jacques PF, Selhub J, Bostom AG, Chen Z, Curtis Ellison R, Eckfeldt JH, Rozen R: The 1298A-->C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine. Atherosclerosis. 2001, 156: 409-415. 10.1016/S0021-9150(00)00671-7.CrossRefPubMed
3.
Zintzaras E: Methylenetetrahydrofolate reductase gene and susceptibility to breast cancer: a meta-analysis. Clinical Genetics. 2006, 69: 327-336. 10.1111/j.1399-0004.2006.00605.x.CrossRefPubMed
4.
Macis D, Maisonneuve P, Johansson H, Bonanni B, Botteri E, Iodice S, Santillo B, Penco S, Gucciardo G, D'Aiuto G, Rosselli Del Turco M, Amadori M, Costa A, Decensi A: Methylenetetrahydrofolate reductase (MTHFR) and breast cancer risk: a nested-case-control study and a pooled meta-analysis. Breast Cancer Res Treat. 2007, 106: 263-271. 10.1007/s10549-006-9491-6.CrossRefPubMed
5.
Lewis SJ, Harbord RM, Harris R, Smith GD: Meta-analyses of observational and genetic association studies of folate intakes or levels and breast cancer risk. Journal of the National Cancer Institute. 2006, 98: 1607-1622.CrossRefPubMed
6.
Maruti SS, Ulrich CM, White E: Folate and one-carbon metabolism nutrients from supplements and diet in relation to breast cancer risk. The American Journal of Clinical Nutrition. 2009, 89: 624-633. 10.3945/ajcn.2008.26568.CrossRefPubMed
7.
White E, Patterson RE, Kristal AR, Thornquist M, King I, Shattuck AL, Evans I, Satia-Abouta J, Littman AJ, Potter JD: VITamins And Lifestyle cohort study: study design and characteristics of supplement users. American Journal of Epidemiology. 2004, 159: 83-93. 10.1093/aje/kwh010.CrossRefPubMed
8.
Diergaarde B, Potter JD, Jupe ER, Manjeshwar S, Shimasaki CD, Pugh TW, Defreese DC, Gramling BA, Evans I, White E: Polymorphisms in genes involved in sex hormone metabolism, estrogen plus progestin hormone therapy use, and risk of postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev. 2008, 17: 1751-1759. 10.1158/1055-9965.EPI-08-0168.CrossRefPubMedPubMedCentral
9.
Patterson RE, Neuhouser ML, White E, Kristal AR, Potter JD: Measurement error from assessing use of vitamin supplements at one point in time. Epidemiology (Cambridge, Mass). 1998, 9: 567-569.CrossRef
10.
Kristal AR, Feng Z, Coates RJ, Oberman A, George V: Associations of race/ethnicity, education, and dietary intervention with the validity and reliability of a food frequency questionnaire: the Women's Health Trial Feasibility Study in Minority Populations. American Journal of Epidemiology. 1997, 146: 856-869.CrossRefPubMed
11.
Patterson RE, Kristal AR, Tinker LF, Carter RA, Bolton MP, Agurs-Collins T: Measurement characteristics of the Women's Health Initiative food frequency questionnaire. Annals of Epidemiology. 1999, 9: 178-187. 10.1016/S1047-2797(98)00055-6.CrossRefPubMed
12.
Satia-Abouta J, Patterson RE, King IB, Stratton KL, Shattuck AL, Kristal AR, Potter JD, Thornquist MD, White E: Reliability and validity of self-report of vitamin and mineral supplement use in the vitamins and lifestyle study. American Journal of Epidemiology. 2003, 157: 944-954. 10.1093/aje/kwg039.CrossRefPubMed
13.
Schakel SF, Buzzard IM, Gebhardt SE: Procedures for estimating nutrient values for food composition databases. J Food Composition Anal. 1997, 10: 102-114. 10.1006/jfca.1997.0527.CrossRef
14.
Dietary reference Intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. 2000, Washington DC: Institute of Medicine, National Academy of Sciences, 210-
15.
Smith-Warner SA, Spiegelman D, Yaun SS, Brandt van den PA, Folsom AR, Goldbohm RA, Graham S, Holmberg L, Howe GR, Marshall JR, Miller AB, Potter JD, Speizer FE, Willett WC, Wolk A, Hunter DJ: Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA. 1998, 279: 535-540. 10.1001/jama.279.7.535.CrossRefPubMed
16.
Campbell IG, Baxter SW, Eccles DM, Choong DY: Methylenetetrahydrofolate reductase polymorphism and susceptibility to breast cancer. Breast Cancer Res. 2002, 4: R14-10.1186/bcr457.CrossRefPubMedPubMedCentral
17.
Semenza JC, Delfino RJ, Ziogas A, Anton-Culver H: Breast cancer risk and methylenetetrahydrofolate reductase polymorphism. Breast Cancer Res Treat. 2003, 77: 217-223. 10.1023/A:1021843019755.CrossRefPubMed
18.
Suzuki T, Matsuo K, Hirose K, Hiraki A, Kawase T, Watanabe M, Yamashita T, Iwata H, Tajima K: One-carbon metabolism-related gene polymorphisms and risk of breast cancer. Carcinogenesis. 2008, 29: 356-362. 10.1093/carcin/bgm295.CrossRefPubMed
19.
Ericson U, Sonestedt E, Ivarsson MI, Gullberg B, Carlson J, Olsson H, Wirfalt E: Folate intake, methylenetetrahydrofolate reductase polymorphisms, and breast cancer risk in women from the Malmo Diet and Cancer cohort. Cancer Epidemiol Biomarkers Prev. 2009, 18: 1101-1110. 10.1158/1055-9965.EPI-08-0401.CrossRefPubMed
20.
Stevens VL, McCullough ML, Pavluck AL, Talbot JT, Feigelson HS, Thun MJ, Calle EE: Association of polymorphisms in one-carbon metabolism genes and postmenopausal breast cancer incidence. Cancer Epidemiol Biomarkers Prev. 2007, 16: 1140-1147. 10.1158/1055-9965.EPI-06-1037.CrossRefPubMed
21.
Shrubsole MJ, Gao YT, Cai Q, Shu XO, Dai Q, Hebert JR, Jin F, Zheng W: MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Epidemiol Biomarkers Prev. 2004, 13: 190-196. 10.1158/1055-9965.EPI-03-0273.CrossRefPubMed
22.
Ma E, Iwasaki M, Junko I, Hamada GS, Nishimoto IN, Carvalho SM, Motola J, Laginha FM, Tsugane S: Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women. BMC Cancer. 2009, 9: 122-10.1186/1471-2407-9-122.CrossRefPubMedPubMedCentral
23.
Chen J, Gammon MD, Chan W, Palomeque C, Wetmur JG, Kabat GC, Teitelbaum SL, Britton JA, Terry MB, Neugut AI, Santella RM: One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer. Cancer Research. 2005, 65: 1606-1614. 10.1158/0008-5472.CAN-04-2630.CrossRefPubMed
24.
Beilby J, Ingram D, Hahnel R, Rossi E: Reduced breast cancer risk with increasing serum folate in a case-control study of the C677T genotype of the methylenetetrahydrofolate reductase gene. Eur J Cancer. 2004, 40: 1250-1254. 10.1016/j.ejca.2004.01.026.CrossRefPubMed
25.
Sharp L, Little J, Schofield AC, Pavlidou E, Cotton SC, Miedzybrodzka Z, Baird JO, Haites NE, Heys SD, Grubb DA: Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR). Cancer Letters. 2002, 181: 65-71. 10.1016/S0304-3835(02)00030-7.CrossRefPubMed
26.
Kotsopoulos J, Zhang WW, Zhang S, McCready D, Trudeau M, Zhang P, Sun P, Narod SA: Polymorphisms in folate metabolizing enzymes and transport proteins and the risk of breast cancer. Breast Cancer Res Treat. 2008, 112: 585-593. 10.1007/s10549-008-9895-6.CrossRefPubMed
27.
Le Marchand L, Haiman CA, Wilkens LR, Kolonel LN, Henderson BE: MTHFR polymorphisms, diet, HRT, and breast cancer risk: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev. 2004, 13: 2071-2077.PubMed
28.
Langsenlehner U, Krippl P, Renner W, Yazdani-Biuki B, Wolf G, Wascher TC, Paulweber B, Weitzer W, Samonigg H: The common 677C>T gene polymorphism of methylenetetrahydrofolate reductase gene is not associated with breast cancer risk. Breast Cancer Res Treat. 2003, 81: 169-172. 10.1023/A:1025752420309.CrossRefPubMed
29.
Justenhoven C, Hamann U, Pierl CB, Rabstein S, Pesch B, Harth V, Baisch C, Vollmert C, Illig T, Bruning T, Ko Y, Brauch H: One-carbon metabolism and breast cancer risk: no association of MTHFR, MTR, and TYMS polymorphisms in the GENICA study from Germany. Cancer Epidemiol Biomarkers Prev. 2005, 14: 3015-3018. 10.1158/1055-9965.EPI-05-0592.CrossRefPubMed
30.
Ergul E, Sazci A, Utkan Z, Canturk NZ: Polymorphisms in the MTHFR gene are associated with breast cancer. Tumour Biol. 2003, 24: 286-290. 10.1159/000076460.CrossRefPubMed
31.
Lee SA, Kang D, Nishio H, Lee MJ, Kim DH, Han W, Yoo KY, Ahn SH, Choe KJ, Hirvonen A, Noh DY: Methylenetetrahydrofolate reductase polymorphism, diet, and breast cancer in Korean women. Experimental & Molecular Medicine. 2004, 36: 116-121.CrossRef
32.
Jakubowska A, Gronwald J, Menkiszak J, Gorski B, Huzarski T, Byrski T, Edler L, Lubinski J, Scott RJ, Hamann U: Methylenetetrahydrofolate reductase polymorphisms modify BRCA1-associated breast and ovarian cancer risks. Breast Cancer Res Treat. 2007, 104: 299-308. 10.1007/s10549-006-9417-3.CrossRefPubMed
33.
Hekim N, Ergen A, Yaylim I, Yilmaz H, Zeybek U, Ozturk O, Isbir T: No association between methylenetetrahydrofolate reductase C677T polymorphism and breast cancer. Cell Biochem and Funct. 2007, 25: 115-117. 10.1002/cbf.1274.CrossRef
34.
Kalemi TG, Lambropoulos AF, Gueorguiev M, Chrisafi S, Papazisis KT, Kotsis A: The association of p53 mutations and p53 codon 72, Her 2 codon 655 and MTHFR C677T polymorphisms with breast cancer in Northern Greece. Cancer Letters. 2005, 222: 57-65. 10.1016/j.canlet.2004.11.025.CrossRefPubMed
35.
Chou YC, Wu MH, Yu JC, Lee MS, Yang T, Shih HL, Wu TY, Sun CA: Genetic polymorphisms of the methylenetetrahydrofolate reductase gene, plasma folate levels and breast cancer susceptibility: a case-control study in Taiwan. Carcinogenesis. 2006, 27: 2295-2300. 10.1093/carcin/bgl108.CrossRefPubMed
36.
Langsenlehner T, Renner W, Yazdani-Biuki B, Langsenlehner U: Methylenetetrahydrofolate reductase (MTHFR) and breast cancer risk: a nested-case-control study and a pooled meta-analysis. Breast Cancer Res Treat. 2007, 107: 459-460. 10.1007/s10549-007-9564-1.CrossRefPubMed
37.
Reljic A, Simundic AM, Topic E, Nikolac N, Justinic D, Stefanovic M: The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and cancer risk: the Croatian case-control study. Clinical Biochemistry. 2007, 40: 981-985. 10.1016/j.clinbiochem.2007.05.005.CrossRefPubMed
38.
Inoue M, Robien K, Wang R, Berg Van Den DJ, Koh WP, Yu MC: Green tea intake, MTHFR/TYMS genotype and breast cancer risk: the Singapore Chinese Health Study. Carcinogenesis. 2008, 29: 1967-1972. 10.1093/carcin/bgn177.CrossRefPubMedPubMedCentral
39.
Yu CP, Wu MH, Chou YC, Yang T, You SL, Chen CJ, Sun CA: Breast cancer risk associated with multigenotypic polymorphisms in folate-metabolizing genes: a nested case-control study in Taiwan. Anticancer Research. 2007, 27: 1727-1732.PubMed
40.
Cheng CW, Yu JC, Huang CS, Shieh JC, Fu YP, Wang HW, Wu PE, Shen CY: Polymorphism of cytosolic serine hydroxymethyltransferase, estrogen and breast cancer risk among Chinese women in Taiwan. Breast Cancer Res Treat. 2008, 111: 145-155. 10.1007/s10549-007-9754-x.CrossRefPubMed
41.
Kundu TK, Rao MR: CpG islands in chromatin organization and gene expression. Journal of Biochemistry. 1999, 125: 217-222.CrossRefPubMed
42.
Lengauer C, Kinzler KW, Vogelstein B: DNA methylation and genetic instability in colorectal cancer cells. Proceedings of the National Academy of Sciences of the United States of America. 1997, 94: 2545-2550. 10.1073/pnas.94.6.2545.CrossRefPubMedPubMedCentral
43.
Jones PA, Baylin SB: The fundamental role of epigenetic events in cancer. Nature Reviews. 2002, 3: 415-428.PubMed
44.
Bariol C, Suter C, Cheong K, Ku SL, Meagher A, Hawkins N, Ward R: The relationship between hypomethylation and CpG island methylation in colorectal neoplasia. The American Journal of Pathology. 2003, 162: 1361-1371.CrossRefPubMedPubMedCentral
45.
Ulrich CM: Nutrigenetics in cancer research--folate metabolism and colorectal cancer. The Journal of Nutrition. 2005, 135: 2698-2702.PubMed
46.
Ulrich CM, Kampman E, Bigler J, Schwartz SM, Chen C, Bostick R, Fosdick L, Beresford SA, Yasui Y, Potter JD: Colorectal adenomas and the C677T MTHFR polymorphism: evidence for gene-environment interaction?. Cancer Epidemiol Biomarkers Prev. 1999, 8: 659-668.PubMed
47.
Friso S, Choi SW, Girelli D, Mason JB, Dolnikowski GG, Bagley PJ, Olivieri O, Jacques PF, Rosenberg IH, Corrocher R, Selhub J: A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proceedings of the National Academy of Sciences of the United States of America. 2002, 99: 5606-5611. 10.1073/pnas.062066299.CrossRefPubMedPubMedCentral
48.
Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, Selhub J, Rozen R: Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996, 93: 7-9.CrossRefPubMed
49.
Ulvik A, Ueland PM, Fredriksen A, Meyer K, Vollset SE, Hoff G, Schneede J: Functional inference of the methylenetetrahydrofolate reductase 677C > T and 1298A > C polymorphisms from a large-scale epidemiological study. Human Genetics. 2007, 121: 57-64. 10.1007/s00439-006-0290-2.CrossRefPubMed
Metadata
Title
MTHFR C677T and postmenopausal breast cancer risk by intakes of one-carbon metabolism nutrients: a nested case-control study
Authors
Sonia S Maruti
Cornelia M Ulrich
Eldon R Jupe
Emily White
Publication date
01-12-2009
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 6/2009
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2462

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