A survey of intragenic breakpoints in glioblastoma identifies a distinct subset associated with poor survival (original) (raw)

  1. Jun Fu2,
  2. Rahulsimham Vegesna1,
  3. Yong Mao1,
  4. Lindsey E. Heathcock3,
  5. Wandaliz Torres-Garcia1,
  6. Ravesanker Ezhilarasan4,
  7. Shuzhen Wang2,
  8. Aaron McKenna5,
  9. Lynda Chin6,
  10. Cameron W. Brennan7,
  11. W.K. Alfred Yung2,
  12. John N. Weinstein1,8,
  13. Kenneth D. Aldape3,
  14. Erik P. Sulman4,
  15. Ken Chen1,
  16. Dimpy Koul2 and
  17. Roel G.W. Verhaak1,9
  18. 1Department of Bioinformatics and Computational Biology,
  19. 2Department of Neuro-Oncology,
  20. 3Department of Pathology,
  21. 4Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  22. 5Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA;
  23. 6Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  24. 7Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
  25. 8Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

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 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.

Footnotes

Freely available online through the Genes & Development Open Access option.