Integrated genomic characterization of IDH1-mutant glioma malignant progression Journal Article

   


Authors: Bai, H.; Harmanci, A. S.; Erson-Omay, E. Z.; Li, J.; Coskun, S.; Simon, M.; Krischek, B.; Özduman, K.; Omay, S. B.; Sorensen, E. A.; Turcan, S.; Bakirciglu, M.; Carrion-Grant, G.; Murray, P. B.; Clark, V. E.; Ercan-Sencicek, A. G.; Knight, J.; Sencar, L.; Altinok, S.; Kaulen, L. D.; Gulez, B.; Timmer, M.; Schramm, J.; Mishra-Gorur, K.; Henegariu, O.; Moliterno, J.; Louvi, A.; Chan, T. A.; Tannheimer, S. L.; Pamir, M. N.; Vortmeyer, A. O.; Bilgüvar, K.; Yasuno, K.; Günel, M.
Article Title: Integrated genomic characterization of IDH1-mutant glioma malignant progression
Abstract: Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors(1). 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.
Keywords: methylation; temozolomide; transcription factors; dna; c-myc; squamous-cell carcinoma; adjuvant; low-grade gliomas; mutational landscape; group protein ezh2; expression profiles; sequencing data
Journal Title: Nature Genetics
Volume: 48
Issue: 1
ISSN: 1061-4036
Publisher: Nature Publishing Group  
Date Published: 2016-01-01
Start Page: 59
End Page: 66
Language: English
ACCESSION: WOS:000367255300014
DOI: 10.1038/ng.3457
PROVIDER: wos
PUBMED: 26618343
PMCID: PMC4829945
Notes: Article -- Source: Wos
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MSK Authors
  1. Timothy Chan
    317 Chan
  2. Sevin Turcan
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