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

Authors: Zheng, Siyuan  Fu, Jun  Vegesna, Rahulsimham  Mao, Yong  Heathcock, Lindsey E  Torres-Garcia, Wandaliz  Ezhilarasan, Ravesanker  Wang, Shuzhen  McKenna, Aaron  Chin, Lynda  Brennan, Cameron W  Yung, W K Alfred  Weinstein, John N  Aldape, Kenneth D  Sulman, Erik P  Chen, Ken  Koul, Dimpy  Verhaak, Roel G W 
Citation: Zheng S, etal., Genes Dev. 2013 Jul 1;27(13):1462-72. doi: 10.1101/gad.213686.113. Epub 2013 Jun 24.
Pubmed: (View Article at PubMed) PMID:23796897
DOI: Full-text: DOI:10.1101/gad.213686.113

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.

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CRRD Object Information
CRRD ID: 13702089
Created: 2018-07-17
Species: All species
Last Modified: 2018-07-17
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.