Cancer Letters

Cancer Letters

Volume 181, Issue 1, 8 July 2002, Pages 65-71
Cancer Letters

Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR)

https://doi.org/10.1016/S0304-3835(02)00030-7Get rights and content

Abstract

Evidence is growing that low folate status may be a factor in the aetiology of several cancers, including breast cancer. The methylenetetrahydrofolate reductase gene (MTHFR), which has a key role in folate metabolism, is polymorphic. We report a case-control study of two functional polymorphisms in MTHFR, dietary folate intake and breast cancer. Sixty-two cases with invasive breast cancer and sixty-six general practice controls participated. Women reporting the highest dietary folate intake had non-significantly reduced breast cancer risk (odds ratio (OR)=0.49, 95% confidence interval (CI) 0.20–1.20). Risk was significantly lower for the 1298CC genotype compared to AA (OR=0.24, 95% CI 0.06–0.97). Relative to compound wild-type subjects, compound heterozygotes had moderately reduced risk (OR=0.47, 95% CI 0.11–1.92) and homozygote variants (677TT and/or 1298CC) greater reduced risk (OR=0.26, 95% CI 0.07–0.96); the trend was statistically significant. Patterns in risk with regard to genotype and folate combinations are broadly similar those reported for colorectal neoplasia. The roles of MTHFR and folate in breast cancer aetiology are likely to be complex.

Introduction

There is growing evidence that low folate status may be a factor in carcinogenesis [1]. There are two mechanisms by which folate deficiency could increase risk of malignancy: (1) by causing DNA hypomethylation and proto-oncogene activation; and/or (2) by inducing uracil misincorporation during DNA synthesis, leading to catastrophic DNA repair, DNA strand breakage and chromosome damage [2]. Although most research has focussed on colorectal cancer [3], the role of folate in the aetiology of other tumours has also been investigated [4], [5], [6], [7], [8] Four recent studies suggest that higher dietary folate intake may be associated with reduced breast cancer risk, particularly among women with a higher alcohol intake [9], [10], [11], [12]. This may reflect the effects of alcohol on folate metabolism [13].

Several genes controlling folate metabolism are polymorphic. 5,10-Methylenetetrahydrofolate reductase (MTHFR) irreversibly converts 5,10-methylenetetrahyrdofolate to 5-methylenetetrahydrofolate, the primary circulating form of folate. Two functional polymorphisms in MTHFR have been reported – C677T and A1298C. For C677T, compared to homozygotes for the common variant, heterozygotes have been reported as having 65% of ‘normal’ enzyme activity and those who are homozygous variant, 30% [14]. Enzyme activity is also decreased in homozygotes for the A1298C variant and, to a lesser extent, in heterozygotes, and in compound heterozygotes for both C677T and A1298C [15]. It is possible that MTHFR polymorphisms might be modifiers of the relationship between dietary folate intake and breast cancer risk. We undertook a case-control study to investigate this.

Section snippets

Ascertainment and recruitment of cases and controls

Women recently diagnosed with breast tumours and being staged for planning of therapy in the Breast Unit of a large teaching hospital (Aberdeen Royal Infirmary) during October 1998–February 1999 were eligible for inclusion in the study. All patients were invited to participate: a total of 65 (81% of those approached) gave signed informed consent and completed a questionnaire and/or provided a mouthwash sample for genotyping. Sixty-two had histologically confirmed invasive breast cancer; the

Results

For reported dietary folate intake, compared to those in the lowest tertile, women in the middle and upper tertiles were at non-significantly reduced risk of breast cancer; risk was lowest in the highest tertile (OR 0.49, 95% CI 0.20–1.20; Table 1). Similarly for vitamin B6, risk was reduced for women in the highest tertile of intake (OR=0.50, 95% CI 0.20–1.21). There was a non-significant trend of increasing risk with increasing vitamin B12 intake.

Five (9.3%) cases and 11 (19.3%) controls were

Discussion

MTHFR has a key role in the metabolism of folate, dietary intake of which has been associated with breast cancer in some studies. Thus, MTHFR polymorphisms may be modifiers of the relationship between folate and breast cancer. To our knowledge, this is the first study to evaluate the role of the two functional polymorphisms in MTHFR in breast cancer. Our findings of a reduced risk associated with the 1298CC genotype and with compound heterozygosity and homozygosity are novel and require

Acknowledgements

We are grateful to the consultants who allowed us to approach their patients for participation in the study and to the two general practitioners who provided us with lists of women from whom to select controls. We are also grateful to the women who took part.

References (38)

  • Z.F Zhang et al.

    Adenocarcinomas of the oesophagus and gastric cardia: the role of diet

    Nutr. Cancer

    (1997)
  • R.Z Stolzenberg-Solomon et al.

    Pancreatic cancer risk and nutrition-related methyl-group availability indicators in male smokers

    J. Natl. Cancer Inst.

    (1999)
  • L.E Voorrips et al.

    A prospective cohort study on antioxidant and folate intake and male lung cancer risk

    Cancer Epidemiol. Biomarkers Prev.

    (2000)
  • S Zhang et al.

    A prospective study of folate intake and the risk of breast cancer

    J. Am. Med. Assoc.

    (1999)
  • T.E Rohan et al.

    Dietary folate consumption and breast cancer risk

    J. Natl. Cancer Inst.

    (2000)
  • E Negri et al.

    Re: dietary folate consumption and breast cancer risk

    J. Natl. Cancer Inst.

    (2000)
  • T.A Sellers et al.

    Dietary folate intake, alcohol, and risk of breast cancer in a study of postmenopausal women

    Epidemiology

    (2001)
  • R Rozen

    Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR)

    Thromb. Haemost.

    (1997)
  • L.F Masson et al.

    Validity of a semi-quantitative food frequency questionnaire compared with 4-day weighed diet records in Scottish men and women

    Proc. Nutr. Soc., (Abstr.)

    (2002)
  • Cited by (0)

    View full text