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Functional Polymorphisms in Folate Metabolism Genes Influence the Risk of Meningioma and Glioma

Sections of ¹ Cancer Genetics and ² Epidemiology, Institute of Cancer Research, Sutton, United Kingdom; ³ Division of Epidemiology, Institute of Environmental Medicine, and ⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; ⁵ Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden; ⁶ Department of Epidemiology, Tampere School of Public Health, University of Tampere, Tampere, Finland; ⁷ Department of Research and Environmental Surveillance, Radiation and Nuclear Safety Authority, Helsinki, Finland; ⁸ Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; ⁹ Division of Epidemiology and Public Health, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, United Kingdom; and ¹⁰ Centre for Epidemiology and Biostatistics, University of Leeds, Leeds, United Kingdom

Requests for reprints: Richard Houlston, Section of Genetics, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom. Phone: 44-208-722-4175; Fax: 44-208-722-4359. E-mail: richard.houlston{at}icr.ac.uk

Folate metabolism plays an important role in carcinogenesis. To test the hypothesis that polymorphic variation in the folate metabolism genes 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) influences the risk of primary brain tumors, we genotyped 1,005 glioma cases, 631 meningioma cases, and 1,101 controls for the MTHFR C677A and A1298C, MTRR A66G, and MTR A2756G variants. MTHFR C677T-A1298C diplotypes were associated with risk of meningioma (P = 0.002) and glioma (P = 0.02); risks were increased with genotypes associated with reduced MTHFR activity. The highest risk of meningioma was associated with heterozygosity for both MTHFR variants [odds ratio (OR), 2.11; 95% confidence interval (95% CI), 1.42-3.12]. The corresponding OR for glioma was 1.23 (95% CI, 0.91-1.66). A significant association between risk of meningioma and homozygosity for MTRR 66G was also observed (OR, 1.41; 95% CI, 1.02-1.94). Our findings provide support for the role of folate metabolism in the development of primary brain tumors. In particular, genotypes associated with increased 5,10-methylenetetrahydrofolate levels are associated with elevated risk. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1195–202)