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Integrated genomic characterization of IDH1-mutant glioma malignant progression

Nature Genetics volume 48, pages 59–66 (2016)Cite this article

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Abstract

Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors1. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.

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Figure 1: Genomic landscape of IDH1-mutant gliomas (n = 82 tumors).
Figure 2: Patterns of nonlinear clonal evolution during glioma progression.
Figure 3: Genomic changes during malignant progression of IDH1-mutant gliomas (n = 41 tumor pairs).
Figure 4: Gene expression during glioma progression (n = 28 tumor pairs).
Figure 5: DNA methylation during glioma progression.
Figure 6: Oncogenic networks during glioma progression and response to BET inhibition.

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Acknowledgements

We are grateful to the patients and their families for donating tissues for this research. This study was supported by the Gregory M. Kiez and Mehmet Kutman Foundation and the Yale University Department of Neurosurgery. Partial funding was provided through a research agreement between Gilead Sciences, Inc., and Yale University.

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Authors and Affiliations

  1. Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA

    Hanwen Bai, Victoria E Clark, James Knight, Ketu Mishra-Gorur, Octavian Henegariu, Kaya Bilguvar & Murat Günel

  2. Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA

    Hanwen Bai, Akdes Serin Harmancı, E Zeynep Erson-Omay, Süleyman Coşkun, S Bülent Omay, Geneive Carrión-Grant, Victoria E Clark, A Gulhan Ercan-Sencicek, Leman Sencar, Selin Altınok, Leon D Kaulen, Burcu Gülez, Ketu Mishra-Gorur, Octavian Henegariu, Jennifer Moliterno, Kaya Bilguvar, Katsuhito Yasuno & Murat Günel

  3. Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA

    Akdes Serin Harmancı, E Zeynep Erson-Omay, Süleyman Coşkun, S Bülent Omay, Geneive Carrión-Grant, Victoria E Clark, A Gulhan Ercan-Sencicek, Leman Sencar, Selin Altınok, Leon D Kaulen, Burcu Gülez, Ketu Mishra-Gorur, Octavian Henegariu, Jennifer Moliterno, Angeliki Louvi, Katsuhito Yasuno & Murat Günel

  4. Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA

    Jie Li & Alexander O Vortmeyer

  5. Department of Neurosurgery, University of Bonn Medical School, Bonn, Germany

    Matthias Simon & Johannes Schramm

  6. Department of General Neurosurgery, University Hospital of Cologne, Cologne, Germany

    Boris Krischek & Marco Timmer

  7. Department of Neurosurgery, Acıbadem University School of Medicine, Istanbul, Turkey

    Koray Özduman, Mehmet Bakırcığlu & M Necmettin Pamir

  8. Translational Medicine, Biomarkers, Gilead Sciences, Inc., Foster City, California, USA

    Eric A Sorensen & Stacey L Tannheimer

  9. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Şevin Turcan & Timothy A Chan

  10. Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA

    Phillip B Murray

  11. Yale Center for Genome Analysis, Yale School of Medicine, Orange, Connecticut, USA

    James Knight & Kaya Bilguvar

  12. Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut, USA

    Ketu Mishra-Gorur, Octavian Henegariu, Angeliki Louvi & Murat Günel

  13. Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut, USA

    Ketu Mishra-Gorur, Octavian Henegariu, Angeliki Louvi, Kaya Bilguvar & Murat Günel

  14. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Timothy A Chan

  15. Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA

    Murat Günel

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  1. Hanwen Bai
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Contributions

H.B., E.Z.E.-O., K.Y. and A.S.H. performed whole-exome sequencing analysis. H.B. and A.S.H. performed exome CNA, SNP array, DNA methylation array and ChIP-seq aggregation analyses. H.B., A.S.H. and K.Y. performed gene expression analysis. H.B. and E.Z.E.-O. performed tumor clonal evolution analysis. H.B. performed trinucleotide mutation signature and oncogenic network analyses. H.B. and K.Y. performed statistical association analysis. A.G.E.-S. and J.K. performed mutation validation. P.B.M. performed NOTCH1 structural analyses. M.S., B.K., M.B., M.N.P., K.Ö., J.S. and M.T. provided samples and clinical data. J.L. and A.O.V. conducted neuropathological evaluations. J.L., H.B., V.E.C. and G.C.-G. prepared samples. K.M.-G., L.S. and O.H. generated patient-derived glioma cultures. S.C., S.B.O., E.A.S., S.L.T. and Ş.T. conducted in vitro drug testing. H.B., S.C., S.B.O., E.A.S., S.L.T., Ş.T. and T.A.C. analyzed drug testing results. K.M.-G., S.A., L.D.K. and B.G. performed RT-qPCR. A.G.E.-S. performed genomic DNA qPCR. K.B. supervised genomic experiments. H.B., M.G., J.M. and A.L. wrote the manuscript, which was reviewed and edited by the other co-authors. M.G. designed and oversaw the project.

Corresponding author

Correspondence to Murat Günel.

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Competing interests

This study was partly supported through a research agreement between Gilead Sciences, Inc., and Yale University. GS-626510 was provided by Gilead. E.A.S. and S.L.T. are employees of Gilead.

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Bai, H., Harmancı, A., Erson-Omay, E. et al. Integrated genomic characterization of IDH1-mutant glioma malignant progression. Nat Genet 48, 59–66 (2016). https://doi.org/10.1038/ng.3457

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