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Genome-wide association study identifies five susceptibility loci for glioma

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Abstract

To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 × 10−17), 8q24.21 (rs4295627, CCDC26; P = 2.34 × 10−18), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 × 10−15), 20q13.33 (rs6010620, RTEL1; P = 2.52 × 10−12) and 11q23.3 (rs498872, PHLDB1; P = 1.07 × 10−8). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.

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Figure 1
Figure 2: LD structure and association results for the five confirmed glioma-associated regions.
Figure 3: Cumulative effects of glioma risk alleles.

Change history

  • 20 July 2009

    In the version of this article initially published online, there were two errors in the author affiliations. For footnote 3, the correct affiliation is “Service de Neurologie Mazarin and UMR 975 INSERM-UPMC, GH Pitié-Salpêtrière, APHP, Paris, France,” rather than “Service de Neurologie Mazarin et INSERM U 711, Hôpital de la Salpêtrière 47, Paris, France.” For author Anders Ahlbom, the correct affiliation is footnote 8 rather than 7. These errors have been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

The Wellcome Trust provided principal funding for the study. In the UK, additional funding was provided by Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) and the European Union (CPRB LSHC-CT-2004-503465). The UK and Swedish INTERPHONE studies were supported by the European Union Fifth Framework Program “Quality of Life and Management of Living Resources” (contract number QLK4-CT-1999-01563) and the International Union against Cancer (UICC). The UICC received funds for this purpose from the Mobile Manufacturers' Forum and Groupe Speciale Mobile (GSM) Association. Provision of funds via the UICC was governed by agreements that guaranteed INTERPHONE's complete scientific independence. These agreements are publicly available at http://www.iarc.fr/en/research-groups/RAD/RCAd.html. The Swedish centre was also supported by the Swedish Research Council, the Cancer Foundation of Northern Sweden, the Swedish Cancer Society, and the Nordic Cancer Union and the UK centre by the Mobile Telecommunications and Health Research (MTHR) Programme and the Health and Safety Executive, Department of Health and Safety Executive and the UK Network Operators (O2, Orange, T-Mobile, Vodafone and '3'). The views expressed in the publication are those of the authors and not necessarily those of the funding bodies. In the United States, funding was provided by US National Institutes of Health grants 5R01 CA119215 and 5R01 CA070917. Additional support was obtained from the American Brain Tumor Association and the National Brain Tumor Society. The University of Texas M.D. Anderson Cancer Center acknowledges the work of P. Adatto, F. Morice, H. Zhang, V. Levin, A. Yung, M. Gilbert, R. Sawaya, V. Puduvalli, C. Conrad, F. Lang and J. Weinberg from the Brain and Spine Center. In France, funding was provided by the Délégation à la Recherche Clinique (MUL03012), the Association pour la Recherche sur les Tumeurs Cérébrales (ARTC), the Institut National du Cancer (INCa; PL 046) and the French Ministry of Higher Education and Research. In Germany, funding was provided to M. Simon, J.S. and M. Linnebank by the Deutsche Forschungsgemeinschaft (Si 552, Schr 285), the Deutsche Krebshilfe (70-2385-Wi2, 70-3163-Wi3, 10-6262) and BONFOR. In Sweden, the collection of samples from the Northern Sweden Health of disease study were collected with support from Umeå University Hospital and NIH funded part of GLIOGENE collection (R01 CA119215). B.M. was supported by Acta Oncologica Foundation as a research fellow at Royal Swedish Academy of Science. In the UK we acknowledge NHS funding to the NIHR Biomedical Research Centre. The UK-GWA study made use of genotyping data on the 1958 Birth Cohort. Genotyping data on controls was generated and generously supplied to us by P. Deloukas (Wellcome Trust Sanger Institute). A full list of the investigators who contributed to the generation of the data are available from http://www.wtccc.org.uk. The US-GWA study made use of control genotypes from the CGEMS prostate and breast cancer studies. A full list of the investigators who contributed to the generation of the data are available from http://cgems.cancer.gov/. The results published here are in whole or part based upon data generated by The Cancer Genome Atlas pilot project established by the National Cancer Institute and National Human Genome Research Institute. Information about TCGA and the investigators and institutions that constitute the TCGA research network can be found at http://cancergenome.nih.gov. Finally, we are grateful to all the study subjects for their participation. We also thank the clinicians and other hospital staff, cancer registries and study staff who contributed to the blood sample and data collection for this study.

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Authors

Contributions

R.S.H. and M.B. designed the study. R.S.H. drafted the manuscript, with extensive contributions from F.J.H. and S.S. F.J.H. and S.S. performed statistical analyses. S.E.D., F.J.H. and S.S. performed bioinformatics analyses. L.B.R. performed laboratory management and oversaw genotyping of UK cases and with A.P. performed genotyping of German and Swedish case-control series. In the UK, A.S., M. Schoemaker, K.M., S.J.H. and R.S.H. developed patient recruitment, sample acquisition and performed sample collection of cases. In the US, M.B. and C.L. developed protocols, M.B. and G.A. developed patient recruitment, G.A., X.G. and R.Y. performed curation and organization of samples and data, and Y.L. performed management of genotyping. In Germany, M. Simon and J.S. developed patient recruitment and blood sample collection, M. Simon oversaw DNA isolation and storage, K.H. and M. Linnebank collected control samples, M. Simon and M. Linnebank performed case ascertainment and supervision of DNA extractions, and K.H. and R.K. procured German control samples. In France, M. Sanson, J.-Y.D., K.H.-X. and A.I. developed patient recruitment, and Y.M., B.B. and S. El-H. developed sample acquisition and performed sample collection of cases. M. Lathrop and D.Z. performed laboratory management and oversaw genotyping of the French samples. In Sweden, for the Swedish INTERPHONE Study, M.F., S.L. and A.A. developed study design and conducted patient recruitment and control selection, M.F., S.L., A.A., B.M. and R.H. organized sample acquisition and performed sample collection of case and controls, U.A. coordinated sample collection and complied information into data files of cases and controls for statistical analyses, and B.M. and R.H. performed laboratory management and oversaw DNA extraction. The NSHDS samples were collected by Umeå University (Principal Investigator Göran Hallmans), and the additional samples were collected at the neurosurgery department in Umeå from 2005 and onwards (A.T.B. and R.H.) and through the national GLIOGENE study (Principal Investigator B.M.). All authors contributed to the final paper.

Corresponding authors

Correspondence to Melissa Bondy or Richard S Houlston.

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Shete, S., Hosking, F., Robertson, L. et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet 41, 899–904 (2009). https://doi.org/10.1038/ng.407

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