Integrated genomic characterization of IDH1-mutant glioma malignant progression

被引：254

作者：

Bai, Hanwen ^{[1
,2
]}

Harmanci, Akdes Serin ^{[2
,3
]}

Erson-Omay, E. Zeynep ^{[2
,3
]}

Li, Jie ^{[4
]}

Coskun, Sueleyman ^{[2
,3
]}

Simon, Matthias ^{[5
]}

Krischek, Boris ^{[6
]}

Ozduman, Koray ^{[7
]}

Omay, S. Buelent ^{[2
,3
]}

Sorensen, Eric A. ^{[8
]}

Turcan, Sevin ^{[9
]}

Bakirciglu, Mehmet ^{[7
]}

Carrion-Grant, Geneive ^{[2
,3
]}

Murray, Phillip B. ^{[10
]}

Clark, Victoria E. ^{[1
,2
,3
]}

Ercan-Sencicek, A. Gulhan ^{[2
,3
]}

Knight, James ^{[1
,11
]}

Sencar, Leman ^{[2
,3
]}

Altinok, Selin ^{[2
,3
]}

Kaulen, Leon D. ^{[2
,3
]}

Guelez, Burcu ^{[2
,3
]}

Timmer, Marco ^{[6
]}

Schramm, Johannes ^{[5
]}

Mishra-Gorur, Ketu ^{[1
,2
,3
,12
,13
]}

Henegariu, Octavian ^{[1
,2
,3
,12
,13
]}

Moliterno, Jennifer ^{[2
,3
]}

Louvi, Angeliki ^{[3
,12
,13
]}

Chan, Timothy A. ^{[9
,14
]}

Tannheimer, Stacey L. ^{[8
]}

Pamir, M. Necmettin ^{[7
]}

Vortmeyer, Alexander O. ^{[4
]}

Bilguvar, Kaya ^{[1
,2
,11
,13
]}

Yasuno, Katsuhito ^{[2
,3
]}

Guenel, Murat ^{[1
,2
,3
,12
,13
,15
]}

机构：

[1] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA

[2] Yale Univ, Sch Med, Program Brain Tumor Res, New Haven, CT USA

[3] Yale Univ, Sch Med, Dept Neurosurg, New Haven, CT USA

[4] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA

[5] Univ Bonn, Sch Med, Dept Neurosurg, Bonn, Germany

[6] Univ Hosp Cologne, Dept Gen Neurosurg, Cologne, Germany

[7] Acibadem Univ, Sch Med, Dept Neurosurg, Istanbul, Turkey

[8] Gilead Sci Inc, Translat Med, Biomarkers, Foster City, CA 94404 USA

[9] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA

[10] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA

[11] Yale Univ, Sch Med, Yale Ctr Genome Anal, Orange, CT USA

[12] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT USA

[13] Yale Univ, Sch Med, Yale Program Neurogenet, New Haven, CT USA

[14] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA

[15] Yale Univ, Sch Med, Yale Comprehens Canc Ctr, New Haven, CT USA

来源：

NATURE GENETICS | 2016年 / 48卷 / 01期

关键词：

GROUP PROTEIN EZH2; MUTATIONAL LANDSCAPE; DNA METHYLATION; ADJUVANT TEMOZOLOMIDE; TRANSCRIPTION FACTORS; SOMATIC MUTATIONS; C-MYC; CANCER; GENE; GLIOBLASTOMA;

D O I：

10.1038/ng.3457

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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.

引用

页码：59 / +

页数：11

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