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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

Abstract

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.

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Acknowledgements

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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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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The authors declare no competing financial interests.

Supplementary information

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). https://doi.org/10.1038/ng.2388

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