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