Integrated genomic characterization of IDH1-mutant glioma malignant progression

Hanwen Bai, Akdes Serin Harmanci, E. Zeynep Erson-Omay, Jie Li, Süleyman Coşkun, Matthias Simon, Boris Krischek, Koray Özduman, S. Bülent Omay, Eric A. Sorensen, Sevin Turcan, Mehmet Bakirciʇlu, Geneive Carrión-Grant, Phillip B. Murray, Victoria E. Clark, A. Gulhan Ercan-Sencicek, James Knight, Leman Sencar, Selin Altinok, Leon D. KaulenBurcu Gülez, Marco Timmer, Johannes Schramm, Ketu Mishra-Gorur, Octavian Henegariu, Jennifer Moliterno, Angeliki Louvi, Timothy A. Chan, Stacey L. Tannheimer, M. Necmettin Pamir, Alexander O. Vortmeyer, Kaya Bilguvar, Katsuhito Yasuno, Murat Günel

Research output: Contribution to journalArticle

126 Scopus citations

Abstract

Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors. 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.

Original languageEnglish (US)
Pages (from-to)59-66
Number of pages8
JournalNature genetics
Volume48
Issue number1
DOIs
StatePublished - Dec 29 2015
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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    Bai, H., Harmanci, A. S., Erson-Omay, E. Z., Li, J., Coşkun, S., Simon, M., Krischek, B., Özduman, K., Omay, S. B., Sorensen, E. A., Turcan, S., Bakirciʇlu, M., Carrión-Grant, G., Murray, P. B., Clark, V. E., Ercan-Sencicek, A. G., Knight, J., Sencar, L., Altinok, S., ... Günel, M. (2015). Integrated genomic characterization of IDH1-mutant glioma malignant progression. Nature genetics, 48(1), 59-66. https://doi.org/10.1038/ng.3457