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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. To understand the molecular mechanisms underlying the malignant progression of low-grade Isocitrate Dehydrogenase 1 (IDH1) mutant gliomas, 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, copy number, gene expression and DNA methylation profiling, demonstrated non-linear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways, up-regulation of the FOXM1- and E2F2-mediated cell cycle transition genes, as well as epigenetic silencing of developmental transcriptional factors 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 extra-terminal (BET) family as a potential therapeutic approach.

PROVIDER: EGAS00001001588 | EGA |

REPOSITORIES: EGA

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Integrated genomic characterization of IDH1-mutant glioma malignant progression.

Bai Hanwen H   Harmancı Akdes Serin AS   Erson-Omay E Zeynep EZ   Li Jie J   Coşkun Süleyman S   Simon Matthias M   Krischek Boris B   Özduman Koray K   Omay S Bülent SB   Sorensen Eric A EA   Turcan Şevin Ş   Bakırcığlu Mehmet M   Carrión-Grant Geneive G   Murray Phillip B PB   Clark Victoria E VE   Ercan-Sencicek A Gulhan AG   Knight James J   Sencar Leman L   Altınok Selin S   Kaulen Leon D LD   Gülez Burcu B   Timmer Marco M   Schramm Johannes J   Mishra-Gorur Ketu K   Henegariu Octavian O   Moliterno Jennifer J   Louvi Angeliki A   Chan Timothy A TA   Tannheimer Stacey L SL   Pamir M Necmettin MN   Vortmeyer Alexander O AO   Bilguvar Kaya K   Yasuno Katsuhito K   Günel Murat M  

Nature genetics 20151130 1


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 me  ...[more]

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