Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The integrated landscape of driver genomic alterations in glioblastoma

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

Subjects

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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.

References

  1. Porter, K.R., McCarthy, B.J., Freels, S., Kim, Y. & Davis, F.G. Prevalence estimates for primary brain tumors in the United States by age, gender, behavior, and histology. Neuro. Oncol. 12, 520–527 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005).

    CAS  PubMed  Google Scholar 

  3. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  4. Noushmehr, H. et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510–522 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Parsons, D.W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Verhaak, R.G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98–110 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bass, A.J. et al. Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nat. Genet. 43, 964–968 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chinnaiyan, A.M. & Palanisamy, N. Chromosomal aberrations in solid tumors. Prog. Mol. Biol. Transl. Sci. 95, 55–94 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Singh, D. et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 337, 1231–1235 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rubin, A.F. & Green, P. Mutation patterns in cancer genomes. Proc. Natl. Acad. Sci. USA 106, 21766–21770 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fan, Z. et al. BCOR regulates mesenchymal stem cell function by epigenetic mechanisms. Nat. Cell Biol. 11, 1002–1009 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wamstad, J.A. & Bardwell, V.J. Characterization of Bcor expression in mouse development. Gene Expr. Patterns 7, 550–557 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wamstad, J.A., Corcoran, C.M., Keating, A.M. & Bardwell, V.J. Role of the transcriptional corepressor Bcor in embryonic stem cell differentiation and early embryonic development. PLoS ONE 3, e2814 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Pugh, T.J. et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 488, 106–110 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhang, J. et al. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 481, 329–334 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kantarci, S. et al. Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes. Nat. Genet. 39, 957–959 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Willnow, T.E. et al. Defective forebrain development in mice lacking gp330/megalin. Proc. Natl. Acad. Sci. USA 93, 8460–8464 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Christ, A. et al. LRP2 is an auxiliary SHH receptor required to condition the forebrain ventral midline for inductive signals. Dev. Cell 22, 268–278 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Cowin, P.A. et al. LRP1B deletion in high-grade serous ovarian cancers is associated with acquired chemotherapy resistance to liposomal doxorubicin. Cancer Res. 72, 4060–4073 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Lima, F.R. et al. Glioblastoma: therapeutic challenges, what lies ahead. Biochim. Biophys. Acta 1826, 338–349 (2012).

    CAS  PubMed  Google Scholar 

  22. Bekker-Jensen, S. et al. HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes. Nat. Cell Biol. 12, 80–86 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Harlalka, G.V. et al. Mutation of HERC2 causes developmental delay with Angelman-like features. J. Med. Genet. 50, 65–73 (2013).

    Article  CAS  PubMed  Google Scholar 

  24. Nacak, T.G., Leptien, K., Fellner, D., Augustin, H.G. & Kroll, J. The BTB-kelch protein LZTR-1 is a novel Golgi protein that is degraded upon induction of apoptosis. J. Biol. Chem. 281, 5065–5071 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Stogios, P.J., Downs, G.S., Jauhal, J.J., Nandra, S.K. & Prive, G.G. Sequence and structural analysis of BTB domain proteins. Genome Biol. 6, R82 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Errington, W.J. et al. Adaptor protein self-assembly drives the control of a cullin-RING ubiquitin ligase. Structure 20, 1141–1153 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Ji, A.X. & Prive, G.G. Crystal structure of KLHL3 in complex with Cullin3. PLoS ONE 8, e60445 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Canning, P. et al. Structural basis for Cul3 assembly with the BTB-Kelch family of E3 ubiquitin ligases. J. Biol. Chem. 288, 7803–7814 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lo, S.C., Li, X., Henzl, M.T., Beamer, L.J. & Hannink, M. Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling. EMBO J. 25, 3605–3617 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Boyden, L.M. et al. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 482, 98–102 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Louis-Dit-Picard, H. et al. KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nat. Genet. 44, 456–460 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Emanuele, M.J. et al. Global identification of modular cullin-RING ligase substrates. Cell 147, 459–474 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Galan, J.M. & Peter, M. Ubiquitin-dependent degradation of multiple F-box proteins by an autocatalytic mechanism. Proc. Natl. Acad. Sci. USA 96, 9124–9129 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhang, D.D. et al. Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. J. Biol. Chem. 280, 30091–30099 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Günther, H.S. et al. Glioblastoma-derived stem cell–enriched cultures form distinct subgroups according to molecular and phenotypic criteria. Oncogene 27, 2897–2909 (2008).

    Article  PubMed  CAS  Google Scholar 

  36. Abu-Elneel, K. et al. A δ-catenin signaling pathway leading to dendritic protrusions. J. Biol. Chem. 283, 32781–32791 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Arikkath, J. et al. δ-catenin regulates spine and synapse morphogenesis and function in hippocampal neurons during development. J. Neurosci. 29, 5435–5442 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kosik, K.S., Donahue, C.P., Israely, I., Liu, X. & Ochiishi, T. δ-catenin at the synaptic-adherens junction. Trends Cell Biol. 15, 172–178 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Israely, I. et al. Deletion of the neuron-specific protein δ-catenin leads to severe cognitive and synaptic dysfunction. Curr. Biol. 14, 1657–1663 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Jun, G. et al. δ-catenin is genetically and biologically associated with cortical cataract and future Alzheimer-related structural and functional brain changes. PLoS ONE 7, e43728 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hicks, S., Wheeler, D.A., Plon, S.E. & Kimmel, M. Prediction of missense mutation functionality depends on both the algorithm and sequence alignment employed. Hum. Mutat. 32, 661–668 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Phillips, H.S. et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9, 157–173 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Carro, M.S. et al. The transcriptional network for mesenchymal transformation of brain tumours. Nature 463, 318–325 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Pierotti, M.A. & Greco, A. Oncogenic rearrangements of the NTRK1/NGF receptor. Cancer Lett. 232, 90–98 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Dunn, G.P. et al. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev. 26, 756–784 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Liu, C. et al. Chemokine receptor CXCR3 promotes growth of glioma. Carcinogenesis 32, 129–137 (2011).

    Article  PubMed  CAS  Google Scholar 

  47. Vivanco, I. et al. Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors. Cancer Discov. 2, 458–471 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Forbes, S.A. et al. COSMIC (the Catalogue of Somatic Mutations in Cancer): a resource to investigate acquired mutations in human cancer. Nucleic Acids Res. 38, D652–D657 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Northcott, P.A. et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 488, 49–56 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tiacci, E. et al. BRAF mutations in hairy-cell leukemia. N. Engl. J. Med. 364, 2305–2315 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Iyer, M.K., Chinnaiyan, A.M. & Maher, C.A. ChimeraScan: a tool for identifying chimeric transcription in sequencing data. Bioinformatics 27, 2903–2904 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Vilella, A.J. et al. EnsemblCompara GeneTrees: complete, duplication-aware phylogenetic trees in vertebrates. Genome Res. 19, 327–335 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Seal, R.L., Gordon, S.M., Lush, M.J., Wright, M.W. & Bruford, E.A. genenames.org: the HGNC resources in 2011. Nucleic Acids Res. 39, D514–D519 (2011).

    Article  CAS  PubMed  Google Scholar 

  54. Danecek, P. et al. The variant call format and VCFtools. Bioinformatics 27, 2156–2158 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Söding, J. Protein homology detection by HMM-HMM comparison. Bioinformatics 21, 951–960 (2005).

    Article  PubMed  Google Scholar 

  57. Roy, A., Kucukural, A. & Zhang, Y. I-TASSER: a unified platform for automated protein structure and function prediction. Nat. Protoc. 5, 725–738 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhuang, M. et al. Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases. Mol. Cell 36, 39–50 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Fülop, V. & Jones, D.T. Beta propellers: structural rigidity and functional diversity. Curr. Opin. Struct. Biol. 9, 715–721 (1999).

    Article  PubMed  Google Scholar 

  60. Tropepe, V. et al. Distinct neural stem cells proliferate in response to EGF and FGF in the developing mouse telencephalon. Dev. Biol. 208, 166–188 (1999).

    Article  CAS  PubMed  Google Scholar 

  61. Niola, F. et al. Id proteins synchronize stemness and anchorage to the niche of neural stem cells. Nat. Cell Biol. 14, 477–487 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Niola, F. et al. Mesenchymal high-grade glioma is maintained by the ID-RAP1 axis. J. Clin. Invest. 123, 405–417 (2013).

    Article  CAS  PubMed  Google Scholar 

  63. Zhao, X. et al. The N-Myc-DLL3 cascade is suppressed by the ubiquitin ligase Huwe1 to inhibit proliferation and promote neurogenesis in the developing brain. Dev. Cell 17, 210–221 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhao, X. et al. The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein. Nat. Cell Biol. 10, 643–653 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Friedman, H.S. et al. Experimental chemotherapy of human medulloblastoma cell lines and transplantable xenografts with bifunctional alkylating agents. Cancer Res. 48, 4189–4195 (1988).

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

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

Authors
  1. Veronique Frattini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vladimir Trifonov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joseph Minhow Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Angelica Castano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marie Lia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Francesco Abate
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stephen T Keir
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alan X Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pietro Zoppoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Francesco Niola
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Carla Danussi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Igor Dolgalev
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Paola Porrati
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Serena Pellegatta
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Adriana Heguy
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Gaurav Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. David J Pisapia
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Peter Canoll
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Jeffrey N Bruce
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Roger E McLendon
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Hai Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Ken Aldape
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Gaetano Finocchiaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Tom Mikkelsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Gilbert G Privé
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Darell D Bigner
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Anna Lasorella
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Raul Rabadan
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Antonio Iavarone
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–15, Supplementary Tables 2, 4–9, 11 and 13–19 (PDF 12178 kb)

Supplementary Table 1

Supplementary Table 1 (XLSX 1503 kb)

Supplementary Table 3

Supplementary Table 3 (XLSX 430 kb)

Supplementary Table 10

Supplementary Table 10 (XLSX 186 kb)

Supplementary Table 12

Supplementary Table 12 (XLSX 50 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2734

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer