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The integrated landscape of driver genomic alterations in glioblastoma

Nature Genetics volume 45, pages 1141–1149 (2013)Cite this article

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Abstract

Glioblastoma is one of the most challenging forms of cancer to treat. Here we describe a computational platform that integrates the analysis of copy number variations and somatic mutations and unravels the landscape of in-frame gene fusions in glioblastoma. We found mutations with loss of heterozygosity in LZTR1, encoding an adaptor of CUL3-containing E3 ligase complexes. Mutations and deletions disrupt LZTR1 function, which restrains the self renewal and growth of glioma spheres that retain stem cell features. Loss-of-function mutations in CTNND2 target a neural-specific gene and are associated with the transformation of glioma cells along the very aggressive mesenchymal phenotype. We also report recurrent translocations that fuse the coding sequence of EGFR to several partners, with EGFR-SEPT14 being the most frequent functional gene fusion in human glioblastoma. EGFR-SEPT14 fusions activate STAT3 signaling and confer mitogen independence and sensitivity to EGFR inhibition. These results provide insights into the pathogenesis of glioblastoma and highlight new targets for therapeutic intervention.

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Figure 1: Chromosome view of validated GBM genes scoring at the top of each of the three categories by MutComFocal.
Figure 2: Interaction with CUL3 and protein stability of wild-type and mutant LZTR1.
Figure 3: Functional analysis of wild-type LZTR1 and GBM-associated mutants in GBM-derived cells.
Figure 4: Expression of δ-catenin in neurons and δ-catenin–driven loss of mesenchymal markers in GBM.
Figure 5: Functional analysis of δ-catenin in mesenchymal GBM.
Figure 6: The EGFR-SEPT14 gene fusion identified by whole-transcriptome sequencing.
Figure 7: Functional analysis of the EGFR-SEPT14 fusion and the effect of inhibition of EGFR kinase on glioma growth.

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Acknowledgements

This work was supported by National Cancer Institute grants R01CA101644 and R01CA131126 (A.L.) and R01CA085628 and R01CA127643 (A.I.), the Stewart Foundation (R.R.), the Partnership for Cure (R.R.), US National Institutes of Health (NIH) grant NIH 1 P50 MH094267-01 (R.R.), the Lymphoma Research Foundation (R.R.), NIH 1 U54 CA121852-05 (R.R.), NIH 1R01CA164152-01 (R.R.), the Leukemia and Lymphoma Society (R.R.), the Canadian Cancer Society (G.G.P.), the Cancer Research Society (G.G.P.), the National Institute of Neurological Disorders and Stroke R01NS061776 (A.I.) and a grant from The Chemotherapy Foundation (A.I.). G.F. was supported by grants from the Associazione Italiana per la Ricerca sul Cancro and from the Italian Ministry of Health. V.F., P.Z., C.D. and F.N. are supported by fellowships from the Italian Ministry of Welfare/Provincia di Benevento and the Federazione Italiana Associazioni Genitori Oncoematologia Pedriatica (FIAGOP) (C.D.). We thank J. Parkinson for helpful discussions on the phylogeny of LZTR1 genes, L. Bertin for help with protein blots, J. Kroll (Tumor Biology Center, Freiburg) for the LZTR1 plasmids and M. Pagano (New York University) for CUL3 expression plasmids.

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Author notes

  1. Francesco Niola

    Present address: Present address: Neuroscience and Brain Technologies, Italian Institute of Technology, Genoa, Italy.,

  2. Veronique Frattini, Vladimir Trifonov, Joseph Minhow Chan, Angelica Castano and Marie Lia: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Cancer Genetics, Columbia University Medical Center, New York, New York, USA

    Veronique Frattini, Angelica Castano, Marie Lia, Pietro Zoppoli, Francesco Niola, Carla Danussi, Anna Lasorella & Antonio Iavarone

  2. Department of Biomedical Informatics, Columbia University Medical Center, New York, New York, USA

    Vladimir Trifonov, Joseph Minhow Chan, Francesco Abate & Raul Rabadan

  3. Department of Systems Biology, Columbia University Medical Center, New York, New York, USA

    Vladimir Trifonov, Joseph Minhow Chan, Francesco Abate & Raul Rabadan

  4. Department of Control and Computer Engineering, Politecnico di Torino, Torino, Italy

    Francesco Abate

  5. The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA

    Stephen T Keir, Roger E McLendon, Hai Yan & Darell D Bigner

  6. The Pediatric Brain Tumor Foundation Institute, Duke University Medical Center, Durham, North Carolina, USA

    Stephen T Keir, Roger E McLendon, Hai Yan & Darell D Bigner

  7. Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA

    Stephen T Keir, Roger E McLendon, Hai Yan & Darell D Bigner

  8. Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada

    Alan X Ji & Gilbert G Privé

  9. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Igor Dolgalev & Adriana Heguy

  10. Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Neurologico C. Besta, Milan, Italy

    Paola Porrati, Serena Pellegatta & Gaetano Finocchiaro

  11. Department of Neurosurgery, Columbia University Medical Center, New York, New York, USA

    Gaurav Gupta & Jeffrey N Bruce

  12. Department of Pathology, Columbia University Medical Center, New York, New York, USA

    David J Pisapia, Peter Canoll, Anna Lasorella & Antonio Iavarone

  13. Department of Pathology, MD Anderson Cancer Center, Houston, Texas, USA

    Ken Aldape

  14. Department of Neurology, Henry Ford Health System, Detroit, Michigan, USA

    Tom Mikkelsen

  15. Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan, USA

    Tom Mikkelsen

  16. Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada

    Gilbert G Privé

  17. Department of Pediatrics, Columbia University Medical Center, New York, New York, USA

    Anna Lasorella

  18. Department of Neurology, Columbia University Medical Center, New York, New York, USA

    Antonio Iavarone

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  1. Veronique Frattini
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Contributions

A.L., R.R. and A.I. conceived the ideas for this study. R.R. designed and supervised the computational approach, and A.L. and A.I. designed and supervised the experimental platform. A.L. performed or assisted in each step of the experimental platform. V.F., A.C., M.L., F.N. and C.D. conducted biological experiments. V.T. performed the MutComFocal analysis. J.M.C. and F.A. performed the gene fusion analysis, allele-specific expression and most of the bioinformatics analyses. P.Z. performed bioinformatics and statistical analyses. S.T.K., H.Y., R.E.M. and D.D.B. performed the human glioma xenograft analyses to evaluate the effects of EGFR inhibitors and provided human GBM specimens. A.X.J. and G.G.P. performed the modeling analysis of LZTR1. I.D. and A.H. conducted the targeted sequencing analysis. P.P., S.P., D.J.P., P.C., J.N.B., K.A., G.G., G.F. and T.M. provided tissue materials from study subjects. A.L., R.R. and A.I. wrote the manuscript with contributions from all other authors.

Corresponding authors

Correspondence to Anna Lasorella, Raul Rabadan or Antonio Iavarone.

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The authors declare no competing financial interests.

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Frattini, V., Trifonov, V., Chan, J. et al. The integrated landscape of driver genomic alterations in glioblastoma. Nat Genet 45, 1141–1149 (2013). https://doi.org/10.1038/ng.2734

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