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

  1. Lara Bethke1,
  2. Emily Webb1,
  3. Anne Murray1,
  4. Minouk Schoemaker2,
  5. Maria Feychting3,
  6. Stefan Lönn4,
  7. Anders Ahlbom3,4,
  8. Beatrice Malmer5,
  9. Roger Henriksson5,
  10. Anssi Auvinen6,7,
  11. Anne Kiuru7,
  12. Tiina Salminen6,7,
  13. Christoffer Johansen8,
  14. Helle Collatz Christensen8,
  15. Kenneth Muir9,
  16. Patricia McKinney10,
  17. Sarah Hepworth10,
  18. Polyxeni Dimitropoulou10,
  19. Artitaya Lophatananon9,
  20. Anthony Swerdlow2 and
  21. Richard Houlston1
  1. Sections of 1Cancer Genetics and 2Epidemiology, Institute of Cancer Research, Sutton, United Kingdom; 3Division of Epidemiology, Institute of Environmental Medicine, and 4Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 5Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden; 6Department of Epidemiology, Tampere School of Public Health, University of Tampere, Tampere, Finland; 7Department of Research and Environmental Surveillance, Radiation and Nuclear Safety Authority, Helsinki, Finland; 8Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; 9Division of Epidemiology and Public Health, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, United Kingdom; and 10Centre for Epidemiology and Biostatistics, University of Leeds, Leeds, United Kingdom
  1. 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

Abstract

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)

Footnotes

  • Grant support: Cancer Research UK. The Interphone Study was supported by the European Commission Fifth Framework Program “Quality of Life and Management of Living Resources” (contract QLK4-CT-1999-01563) and the International Union against Cancer (RCA/01/08). The International Union against Cancer received funds for this study from the Mobile Manufacturers' Forum and the Global System for Mobile Communications Association. Provision of funds to the Interphone study investigators via International Union against Cancer was governed by agreements that guaranteed Interphone's complete scientific independence. These agreements are publicly available at http://www.iarc.fr/ENG/Units/RCAd.html. Additional support was given to the Danish partner by the Danish Cancer Society. The Finnish partner received further financing from the Emil Aaltonen Foundation and Finnish Cancer Organisations, The Swedish partner received additional grant funding from the Swedish Research Council, The Swedish Cancer Society, and the Cancer Foundation of Northern Sweden. The UK-Southeast and Northern centers were also supported by the Mobile Telecommunications and Health Research Program and the UK-North was supported by the Health and Safety Executive, Department of Health and Safety Executive and the UK Network Operators (O2, Orange, T-Mobile, Vodafone, and “3”).

  • Note: Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/).

    • Accepted February 8, 2008.
    • Received October 25, 2007.
    • Revision received January 30, 2008.
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  1. doi: 10.1158/1055-9965.EPI-07-2733 Cancer Epidemiology, Biomarkers & Prevention May 1, 2008 17, 1195
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