A survey of intragenic breakpoints in glioblastoma identifies a distinct subset associated with poor survival

被引：58

作者：

Zheng, Siyuan ^{[1
]}

Fu, Jun ^{[2
]}

Vegesna, Rahulsimham ^{[1
]}

Mao, Yong ^{[1
]}

Heathcock, Lindsey E. ^{[3
]}

Torres-Garcia, Wandaliz ^{[1
]}

Ezhilarasan, Ravesanker ^{[4
]}

Wang, Shuzhen ^{[2
]}

McKenna, Aaron ^{[5
]}

Chin, Lynda ^{[6
]}

Brennan, Cameron W. ^{[7
]}

Yung, W. K. Alfred ^{[2
]}

Weinstein, John N. ^{[1
,8
]}

Aldape, Kenneth D. ^{[3
]}

Sulman, Erik P. ^{[4
]}

Chen, Ken ^{[1
]}

Koul, Dimpy ^{[2
]}

Verhaak, Roel G. W. ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA

[5] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA 02142 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[7] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10065 USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

来源：

GENES & DEVELOPMENT | 2013年 / 27卷 / 13期

关键词：

Glioblastoma multiforme; The Cancer Genome Atlas; intragenic breakpoint; gene fusion; genomic rearrangement; genomic instability; DOUBLE-MINUTE CHROMOSOMES; INTEGRATED GENOMIC ANALYSIS; FACTOR RECEPTOR GENE; INTRATUMOR HETEROGENEITY; TUMOR-SUPPRESSOR; CANCER; AMPLIFICATION; GLIOMA; EGFR; ALGORITHM;

D O I：

10.1101/gad.213686.113

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

With the advent of high-throughput sequencing technologies, much progress has been made in the identification of somatic structural rearrangements in cancer genomes. However, characterization of the complex alterations and their associated mechanisms remains inadequate. Here, we report a comprehensive analysis of whole-genome sequencing and DNA copy number data sets from The Cancer Genome Atlas to relate chromosomal alterations to imbalances in DNA dosage and describe the landscape of intragenic breakpoints in glioblastoma multiforme (GBM). Gene length, guanine-cytosine (GC) content, and local presence of a copy number alteration were closely associated with breakpoint susceptibility. A dense pattern of repeated focal amplifications involving the murine double minute 2 (MDM2)/cyclin-dependent kinase 4 (CDK4) oncogenes and associated with poor survival was identified in 5% of GBMs. Gene fusions and rearrangements were detected concomitant within the breakpoint-enriched region. At the gene level, we noted recurrent breakpoints in genes such as apoptosis regulator FAF1. Structural alterations of the FAF1 gene disrupted expression and led to protein depletion. Restoration of the FAF1 protein in glioma cell lines significantly increased the FAS-mediated apoptosis response. Our study uncovered a previously underappreciated genomic mechanism of gene deregulation that can confer growth advantages on tumor cells and may generate cancer-specific vulnerabilities in subsets of GBM.

引用

页码：1462 / 1472

页数：11

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