TY - JOUR
T1 - A survey of intragenic breakpoints in glioblastoma identifies a distinct subset associated with poor survival
AU - Zheng, Siyuan
AU - Fu, Jun
AU - Vegesna, Rahulsimham
AU - Mao, Yong
AU - Heathcock, Lindsey E.
AU - Torres-Garcia, Wandaliz
AU - Ezhilarasan, Ravesanker
AU - Wang, Shuzhen
AU - McKenna, Aaron
AU - Chin, Lynda
AU - Brennan, Cameron W.
AU - Alfred Yung, W. K.
AU - Weinstein, John N.
AU - Aldape, Kenneth D.
AU - Sulman, Erik P.
AU - Chen, Ken
AU - Koul, Dimpy
AU - Verhaak, Roel G.W.
PY - 2013/7/1
Y1 - 2013/7/1
N2 - 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 breakpointenriched 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.
AB - 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 breakpointenriched 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.
KW - Gene fusion
KW - Genomic instability
KW - Genomic rearrangement
KW - Glioblastoma multiforme
KW - Intragenic breakpoint
KW - The Cancer Genome Atlas
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U2 - 10.1101/gad.213686.113
DO - 10.1101/gad.213686.113
M3 - Article
C2 - 23796897
AN - SCOPUS:84879764400
SN - 0890-9369
VL - 27
SP - 1462
EP - 1472
JO - Genes and Development
JF - Genes and Development
IS - 13
ER -