title: Whole genome sequencing of glioblastoma multiforme identifies multiple structural variations involved in EGFR activation.
abstract: Next generation sequencing has become a powerful tool in dissecting and identifying mutations and genomic structural variants that accompany tumourigenesis. Sequence analysis of glioblastoma multiforme (GBM) illustrates the ability to rapidly identify mutations that may affect phenotype. Approximately 50% of human GBMs overexpress epidermal growth factor receptor (EGFR) which renders the EGFR protein a compelling therapeutic target. In brain tumours, attempts to target EGFR as a cancer therapeutic, however, have achieved little or no benefit. The mechanisms that drive therapeutic resistance to EGFR inhibitors in brain tumours are not well defined, and drug resistance contributes to the deadly and aggressive nature of the disease. Whole genome sequencing of four primary GBMs revealed multiple pathways by which EGFR protein abundance becomes deregulated in these tumours and will guide the development of new strategies for treating EGFR overexpressing tumours. Each of the four tumours displayed a different mechanism leading to increased EGFR protein levels. One mechanism is mediated by gene amplification and tandem duplication of the kinase domain. A second involves an intragenic deletion that generates a constitutively active form of the protein. A third combines the loss of a gene which encodes a protein that regulates EGFR abundance as well as an miRNA that modulates EGFR expression. A fourth mechanism entails loss of an ubiquitin ligase docking site in the C-terminal part of the protein whose absence inhibits turnover of the receptor.
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Cincinnati College of Medicine, 231, Albert Sabin Way, Cincinnati, OH, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Furgason
authors.affiliation: Albert Einstein Medical Center, 1301 Morris Park Avenue, New York, NY, USA.
authors.forename: Wenge
authors.initials: W
authors.lastname: Li
authors.affiliation: Albert Einstein Medical Center, 1301 Morris Park Avenue, New York, NY, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Milholland
authors.affiliation: Department of Molecular Genetics, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Cross
authors.affiliation: Department of Molecular Genetics, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, USA.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurosurgery and UC Brain Tumor Center, University of Cincinnati, 234 Goodman Street, Cincinnati, OH, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: McPherson
authors.affiliation: Department of Neurosurgery and UC Brain Tumor Center, University of Cincinnati, 234 Goodman Street, Cincinnati, OH, USA.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Warnick
authors.affiliation: GRU Cancer Center, 1411 Laney Walker Boulevard Augusta, GA, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rixe
authors.affiliation: Department of Molecular Genetics, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Stambrook
authors.affiliation: Albert Einstein Medical Center, 1301 Morris Park Avenue, New York, NY, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Vijg
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Cincinnati College of Medicine, 231, Albert Sabin Way, Cincinnati, OH, USA, UC Brain Tumor Center, University of Cincinnati, 234 Goodman Street, Cincinnati, OH, USA, bhassiem@uc.edu.
authors.forename: El Mustapha
authors.initials: el M
authors.lastname: Bahassi
mesh_terms: D000595:Amino Acid Sequence; D001932:Brain Neoplasms / Q000235:genetics; D056915:DNA Copy Number Variations; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005784:Gene Amplification; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D015723:Gene Library; D005909:Glioblastoma / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA
chemical_list: D035683:MicroRNAs; C512478:EGFR protein, human; D066246:ErbB Receptors
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