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

Siyuan Zheng, Jun Fu, Rahulsimham Vegesna, Yong Mao, Lindsey E. Heathcock, Wandaliz Torres-Garcia, Ravesanker Ezhilarasan, Shuzhen Wang, Aaron McKenna, Lynda Chin, Cameron W. Brennan, W. K. Alfred Yung, John N. Weinstein, Kenneth D. Aldape, Erik P. Sulman, Ken Chen, Dimpy Koul, Roel G.W. Verhaak

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1462-1472
Number of pages11
JournalGenes and Development
Volume27
Issue number13
DOIs
StatePublished - Jul 1 2013

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Keywords

  • Gene fusion
  • Genomic instability
  • Genomic rearrangement
  • Glioblastoma multiforme
  • Intragenic breakpoint
  • The Cancer Genome Atlas

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Zheng, S., Fu, J., Vegesna, R., Mao, Y., Heathcock, L. E., Torres-Garcia, W., Ezhilarasan, R., Wang, S., McKenna, A., Chin, L., Brennan, C. W., Alfred Yung, W. K., Weinstein, J. N., Aldape, K. D., Sulman, E. P., Chen, K., Koul, D., & Verhaak, R. G. W. (2013). A survey of intragenic breakpoints in glioblastoma identifies a distinct subset associated with poor survival. Genes and Development, 27(13), 1462-1472. https://doi.org/10.1101/gad.213686.113