Whole genome sequencing of glioblastoma multiforme identifies multiple structural variations involved in EGFR activation

John M. Furgason, Wenge Li, Brandon Milholland, Emily Cross, Yaqin Li, Christopher M. McPherson, Ronald E. Warnick, Olivier Rixe, Peter J. Stambrook, Jan Vijg, El Mustapha Bahassi

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)341-350
Number of pages10
JournalMutagenesis
Volume29
Issue number5
DOIs
StatePublished - 2014

Fingerprint

Glioblastoma
Epidermal Growth Factor Receptor
Genes
Chemical activation
Genome
Tumors
Proteins
Brain Neoplasms
Genomic Structural Variation
Brain
Neoplasms
Mutation
Gene Amplification
Ligases
Ubiquitin
MicroRNAs
Drug Resistance
Sequence Analysis
Phosphotransferases
Therapeutics

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Whole genome sequencing of glioblastoma multiforme identifies multiple structural variations involved in EGFR activation. / Furgason, John M.; Li, Wenge; Milholland, Brandon; Cross, Emily; Li, Yaqin; McPherson, Christopher M.; Warnick, Ronald E.; Rixe, Olivier; Stambrook, Peter J.; Vijg, Jan; Bahassi, El Mustapha.

In: Mutagenesis, Vol. 29, No. 5, 2014, p. 341-350.

Research output: Contribution to journalArticle

Furgason, JM, Li, W, Milholland, B, Cross, E, Li, Y, McPherson, CM, Warnick, RE, Rixe, O, Stambrook, PJ, Vijg, J & Bahassi, EM 2014, 'Whole genome sequencing of glioblastoma multiforme identifies multiple structural variations involved in EGFR activation', Mutagenesis, vol. 29, no. 5, pp. 341-350. https://doi.org/10.1093/mutage/geu026
Furgason, John M. ; Li, Wenge ; Milholland, Brandon ; Cross, Emily ; Li, Yaqin ; McPherson, Christopher M. ; Warnick, Ronald E. ; Rixe, Olivier ; Stambrook, Peter J. ; Vijg, Jan ; Bahassi, El Mustapha. / Whole genome sequencing of glioblastoma multiforme identifies multiple structural variations involved in EGFR activation. In: Mutagenesis. 2014 ; Vol. 29, No. 5. pp. 341-350.
@article{1ea42c7d44a542bfa97cd709100b23bc,
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.",
author = "Furgason, {John M.} and Wenge Li and Brandon Milholland and Emily Cross and Yaqin Li and McPherson, {Christopher M.} and Warnick, {Ronald E.} and Olivier Rixe and Stambrook, {Peter J.} and Jan Vijg and Bahassi, {El Mustapha}",
year = "2014",
doi = "10.1093/mutage/geu026",
language = "English (US)",
volume = "29",
pages = "341--350",
journal = "Mutagenesis",
issn = "0267-8357",
publisher = "Oxford University Press",
number = "5",

}

TY - JOUR

T1 - Whole genome sequencing of glioblastoma multiforme identifies multiple structural variations involved in EGFR activation

AU - Furgason, John M.

AU - Li, Wenge

AU - Milholland, Brandon

AU - Cross, Emily

AU - Li, Yaqin

AU - McPherson, Christopher M.

AU - Warnick, Ronald E.

AU - Rixe, Olivier

AU - Stambrook, Peter J.

AU - Vijg, Jan

AU - Bahassi, El Mustapha

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84906812646&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84906812646&partnerID=8YFLogxK

U2 - 10.1093/mutage/geu026

DO - 10.1093/mutage/geu026

M3 - Article

C2 - 25103728

AN - SCOPUS:84906812646

VL - 29

SP - 341

EP - 350

JO - Mutagenesis

JF - Mutagenesis

SN - 0267-8357

IS - 5

ER -