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A low-frequency variant at 8q24.21 is strongly associated with risk of oligodendroglial tumors and astrocytomas with IDH1 or IDH2 mutation


Variants at 8q24.21 have been shown to be associated with glioma development. By means of tag SNP genotyping and imputation, pooled next-generation sequencing using long-range PCR and subsequent validation SNP genotyping, we identified seven low-frequency SNPs at 8q24.21 that were strongly associated with glioma risk (P = 1 × 10−25 to 1 × 10−14). The most strongly associated SNP, rs55705857, remained highly significant after individual adjustment for the other top six SNPs and two previously published SNPs. After stratifying by histological and tumor genetic subtype, the most significant associations of rs55705857 were with oligodendroglial tumors and gliomas with mutant IDH1 or IDH2 (odds ratio (OR) = 5.1, P = 1.1 × 10−31 and OR = 4.8, P = 6.6 × 10−22, respectively). Strong associations were observed for astrocytomas with mutated IDH1 or IDH2 (grades 2–4) (OR = 5.16–6.66, P = 4.7 × 10−12 to 2.2 × 10−8) but not for astrocytomas with wild-type IDH1 and IDH2 (smallest P = 0.26). The conserved sequence block that includes rs55705857 is consistently modeled as a microRNA.

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Figure 1: Case-control SNP associations with oligodendroglioma risk for 157 SNPs within the 8q24.21 (CCDC26) region by study site.
Figure 2: Glioma case-control ORs, 95% confidence intervals and −log10P values for SNPs within the 8q24.21 (CCDC26) region.


  1. Shete, S. et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat. Genet. 41, 899–904 (2009).

    Article  CAS  Google Scholar 

  2. Jenkins, R.B. et al. Distinct germ line polymorphisms underlie glioma morphologic heterogeneity. Cancer Genet. 204, 13–18 (2011).

    Article  Google Scholar 

  3. Sanson, M. et al. Chromosome 7p11.2 (EGFR) variation influences glioma risk. Hum. Mol. Genet. 20, 2897–2904 (2011).

    Article  CAS  Google Scholar 

  4. Rice, T. et al. Associations of glioma risk loci by IDH1 mutation status. Neuro-oncol. 13 (suppl. 3), iii27 (2011).

    Google Scholar 

  5. Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).

    Article  CAS  Google Scholar 

  6. Christensen, B.C. et al. DNA methylation, isocitrate dehydrogenase mutation, and survival in glioma. J. Natl. Cancer Inst. 103, 143–153 (2011).

    Article  CAS  Google Scholar 

  7. Houillier, C. et al. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology 75, 1560–1566 (2010).

    Article  CAS  Google Scholar 

  8. van den Bent, M.J. et al. IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors, a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Clin. Cancer Res. 16, 1597–1604 (2010).

    Article  CAS  Google Scholar 

  9. Hartmann, C. et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age, a study of 1,010 diffuse gliomas. Acta Neuropathol. 118, 469–474 (2009).

    Article  Google Scholar 

  10. Cairncross, G. et al. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma, Intergroup Radiation Therapy Oncology Group Trial 9402. J. Clin. Oncol. 24, 2707–2714 (2006).

    Article  CAS  Google Scholar 

  11. Idbaih, A. et al. Genomic aberrations associated with outcome in anaplastic oligodendroglial tumors treated within the EORTC phase III trial 26951. J. Neurooncol. 103, 221–230 (2011).

    Article  CAS  Google Scholar 

  12. Teerlink, C. et al. A unique genome-wide association analysis in extended Utah high-risk pedigrees identifies a novel melanoma risk variant on chromosome arm 10q. Hum. Genet. 131, 77–85 (2012).

    Article  CAS  Google Scholar 

  13. Sato, Y. et al. Genome-wide association study on overall survival of advanced non-small cell lung cancer patients treated with carboplatin and paclitaxel. J. Thorac. Oncol. 6, 132–138 (2011).

    Article  Google Scholar 

  14. Low, S.K. et al. Genome-wide association study of pancreatic cancer in Japanese population. PLoS ONE 5, e11824 (2010).

    Article  Google Scholar 

  15. Treviño, L.R. et al. Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat. Genet. 41, 1001–1005 (2009).

    Article  Google Scholar 

  16. Mu, W. & Zhang, W. Bioinformatic resources of microRNA sequences, gene targets, and genetic variation. Front. Genet. 3, 31 (2012).

    Article  CAS  Google Scholar 

  17. Stevens, K.N. et al. 19p13.1 is a triple negative–specific breast cancer susceptibility locus. Cancer Res. 72, 1795–1803 (2012).

    Article  CAS  Google Scholar 

  18. Truong, T. et al. Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium. J. Natl. Cancer Inst. 102, 959–971 (2010).

    Article  CAS  Google Scholar 

  19. Goode, E.L. et al. A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat. Genet. 42, 874–879 (2010).

    Article  CAS  Google Scholar 

  20. Gayther, S.A. & Pharoah, P.D. The inherited genetics of ovarian and endometrial cancer. Curr. Opin. Genet. Dev. 20, 231–238 (2010).

    Article  CAS  Google Scholar 

  21. Al Olama, A.A. et al. Multiple loci on 8q24 associated with prostate cancer susceptibility. Nat. Genet. 41, 1058–1060 (2009).

    Article  CAS  Google Scholar 

  22. Gudmundsson, J. et al. Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility. Nat. Genet. 41, 1122–1126 (2009).

    Article  CAS  Google Scholar 

  23. Ghoussaini, M. et al. Multiple loci with different cancer specificities within the 8q24 gene desert. J. Natl. Cancer Inst. 100, 962–966 (2008).

    Article  CAS  Google Scholar 

  24. Wang, K. et al. Interpretation of association signals and identification of causal variants from genome-wide association studies. Am. J. Hum. Genet. 86, 730–742 (2010).

    Article  CAS  Google Scholar 

  25. Noushmehr, H. et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510–522 (2010).

    Article  CAS  Google Scholar 

  26. Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).

    Article  CAS  Google Scholar 

  27. Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012).

    Article  CAS  Google Scholar 

  28. Wrensch, M. et al. Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility. Nat. Genet. 41, 905–908 (2009).

    Article  CAS  Google Scholar 

  29. Felini, M.J. et al. Reproductive factors and hormone use and risk of adult gliomas. Cancer Causes Control 20, 87–96 (2009).

    Article  Google Scholar 

  30. Wrensch, M. et al. Nonsynonymous coding single-nucleotide polymorphisms spanning the genome in relation to glioblastoma survival and age at diagnosis. Clin. Cancer Res. 13, 197–205 (2007).

    Article  CAS  Google Scholar 

  31. Smith, J.S. et al. Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. J. Clin. Oncol. 18, 636–645 (2000).

    Article  CAS  Google Scholar 

  32. Li, Y., Willer, C., Sanna, S. & Abecasis, G. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).

    Article  CAS  Google Scholar 

  33. Purcell, S. et al. PLINK: a toolset for whole-genome association and population-based linkage analysis. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  34. Browning, B.L. & Browning, S.R. A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am. J. Hum. Genet. 84, 210–223 (2009).

    Article  CAS  Google Scholar 

  35. Ding, Y., Chan, C.Y. & Lawrence, C.E. RNA secondary structure prediction by centroids in a Boltzmann weighted ensemble. RNA 11, 1157–1166 (2005).

    Article  CAS  Google Scholar 

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The authors wish to acknowledge study participants, the clinicians and research staff at the participating medical centers, deCODE Genetics, the late Bernd Scheithauer, the Mayo Clinic Comprehensive Cancer Center Biospecimens Accessioning and Processing Shared Resource and Genotyping Shared Resource and the UCSF Diller Cancer Center Genomics Core. Work at the Mayo Clinic was supported by the US National Institutes of Health (NIH; grants P50CA108961 and P30CA15083), the National Institute of Neurological Disorders and Stroke (grant RC1NS068222Z), the Bernie and Edith Waterman Foundation and the Ting Tsung and Wei Fong Chao Family Foundation. Work at the University of California, San Francisco, was supported by the NIH (grants R01CA52689, P50CA097257, R01CA126831 and R25CA112355), as well as the National Brain Tumor Foundation and the UCSF Lewis Chair in Brain Tumor Research, and by donations from families and friends of John Berardi, Helen Glaser, Elvera Olsen, Raymond E. Cooper and William Martinusen.

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Authors and Affiliations



R.B.J. and D.H.L. led the study at the Mayo Clinic, and M.R.W. and J.K.W. led the study at UCSF. R.B.J., M.R.W., D.H.L., J.K.W., J.E.E.-P., Y.X., H.S., T.M.K., T.R., H.M.H. and P.B. contributed to manuscript preparation. Study coordination was the responsibility of S.R.F. and T.M.K. at the Mayo Clinic, and T.R. and L.S.M. at UCSF. Y.X., J.E.E.-P., H.S., K.M.W. and B.L.F. co-directed and conducted biostatistics and bioinformatics analyses, with additional support from P.A.D., M.L.K., I.S. and A.R.P. Laboratory work was performed by T.M.K., A.L.R., C.H., A.A.C. and S.R.F. under the direction of R.B.J. at the Mayo Clinic and by H.M.H., S.Z., J.S.P. and G.H. under the direction of J.K.W., J.L.W. and M.R.W. at UCSF. Pathology support, including pathology review, was provided by C.G. and T.T. Subject enrollment and clinical record review was performed or facilitated by M.D.P., S.M.C., M.S.B., J.C.B., B.P.O. and D.H.L.

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Correspondence to Robert B Jenkins.

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Supplementary Text and Figures

Supplementary Tables 1 and 3–5 and Supplementary Figures 1–5 (PDF 6891 kb)

Supplementary Table 2

Stage 2 validation genotyping and glioma case-control association results for 157 candidate SNPs in the chromosome 8q24.21 (CCDC26) region (XLS 87 kb)

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Jenkins, R., Xiao, Y., Sicotte, H. et al. A low-frequency variant at 8q24.21 is strongly associated with risk of oligodendroglial tumors and astrocytomas with IDH1 or IDH2 mutation. Nat Genet 44, 1122–1125 (2012).

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