Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma.

Tumor heterogeneity has been implicated in tumor growth and progression as well as resistance to therapy. We present an example of genetic heterogeneity in human malignant brain tumors in which multiple closely related driver genes are amplified and activated simultaneously in adjacent intermingled cells. We have observed up to three different receptor tyrosine kinases (EGFR, MET, PDGFRA) amplified in single tumors in different cells in a mutually exclusive fashion. Each subpopulation was actively dividing, and the genetic changes resulted in protein production, and coexisting subpopulations shared common early genetic mutations indicating their derivation from a single precursor cell. The stable coexistence of different clones within the same tumor will have important clinical implications for tumor resistance to targeted therapies.

[1]  M. Nicholas,et al.  Glioblastoma multiforme: evidence-based approach to therapy , 2007, Expert review of anticancer therapy.

[2]  B. Scheithauer,et al.  The 2007 WHO classification of tumours of the central nervous system , 2007, Acta Neuropathologica.

[3]  W. Yung,et al.  Safety and efficacy of erlotinib in first-relapse glioblastoma: a phase II open-label study. , 2010, Neuro-oncology.

[4]  H. Joensuu,et al.  Amplification of genes encoding KIT, PDGFRα and VEGFR2 receptor tyrosine kinases is frequent in glioblastoma multiforme , 2005, The Journal of pathology.

[5]  A. Paetau,et al.  Amplification of KIT, PDGFRA, VEGFR2, and EGFR in Gliomas , 2006, Molecular Cancer Research.

[6]  N. Carter,et al.  Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development , 2011, Cell.

[7]  J. Uhm.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2009 .

[8]  Catherine L Nutt,et al.  Selection pressures of TP53 mutation and microenvironmental location influence epidermal growth factor receptor gene amplification in human glioblastomas. , 2003, Cancer research.

[9]  G. Broggi,et al.  Genetic alterations and in vivo tumorigenicity of neurospheres derived from an adult glioblastoma , 2004, Molecular Cancer.

[10]  Camille Stephan-Otto Attolini,et al.  A mathematical framework to determine the temporal sequence of somatic genetic events in cancer , 2010, Proceedings of the National Academy of Sciences.

[11]  M. Roizen,et al.  Hallmarks of Cancer: The Next Generation , 2012 .

[12]  K. Polyak,et al.  Tumor heterogeneity: causes and consequences. , 2010, Biochimica et biophysica acta.

[13]  B. Wullich,et al.  Amplified met gene linked to double minutes in human glioblastoma. , 1993, European journal of cancer.

[14]  D. Haber,et al.  Cancer: Drivers and passengers , 2007, Nature.

[15]  A. Gregory Sorensen,et al.  Angiogenesis in brain tumours , 2007, Nature Reviews Neuroscience.

[16]  J. Alsner,et al.  An evolutionary-game model of tumour-cell interactions: possible relevance to gene therapy. , 2001, European journal of cancer.

[17]  M. Gerlinger,et al.  How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine , 2010, British Journal of Cancer.

[18]  J. Troge,et al.  Tumour evolution inferred by single-cell sequencing , 2011, Nature.

[19]  J. Troge,et al.  Inferring tumor progression from genomic heterogeneity. , 2010, Genome research.

[20]  M. Nowak,et al.  Distant Metastasis Occurs Late during the Genetic Evolution of Pancreatic Cancer , 2010, Nature.

[21]  M. Nicholas,et al.  Molecular heterogeneity in glioblastoma: therapeutic opportunities and challenges. , 2011, Seminars in oncology.

[22]  Stephen Yip,et al.  MSH6 Mutations Arise in Glioblastomas during Temozolomide Therapy and Mediate Temozolomide Resistance , 2009, Clinical Cancer Research.