Primary glioblastomas with and without EGFR amplification: Relationship to genetic alterations and clinicopathological features

Benito, Rafael; Gil-Benso, Rosario; Quilis, Vicente; Pérez, Manuel Asensi; Gregori-Romero, Mariela; Roldán, Pedro; González-Darder, José M.; Cerdá-Nicolás, Miguel; López‐Ginés, Concha

doi:10.1111/j.1440-1789.2009.01081.x

Cited by 38 publications

(33 citation statements)

References 22 publications

(66 reference statements)

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“…About 40% of all GBMs have EGFR amplification, and it is more common in primary as compared to secondary GBMs (7–9, 124, 125). There is experimental evidence that EGFR amplification may result in a less favorable prognosis; however, clinical studies are inconclusive (72, 117, 118).…”

Section: Prognostic Molecular Markers In Gbmmentioning

confidence: 99%

Epidemiologic and Molecular Prognostic Review of Glioblastoma

Thakkar

Dolecek

Horbinski

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

995

776

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Glioblastoma (GBM) is the most common and aggressive primary CNS malignancy with a median survival of 15 months. The average incidence rate (IR) of GBM is 3.19/100,000 population and the median age of diagnosis is 64 years. Incidence is higher in men and individuals of white race and non-Hispanic ethnicity. Many genetic and environmental factors have been studied in GBM but the majority are sporadic and no risk factor accounting for a large proportion of GBMs has been identified. However, several favorable clinical prognostic factors are identified including, younger age at diagnosis, cerebellar location, high performance status and maximal tumor resection. GBMs comprise of primary and secondary subtypes which evolve through different genetic pathways, affect patients at different ages and have differences in outcomes. We report the current epidemiology of GBM with new data from the Central Brain Tumor Registry of the United States (CBTRUS) 2006–2010 as well as demonstrate and discuss trends in incidence and survival. We also provide a concise review on molecular markers in GBM that have helped distinguish biologically similar subtypes of GBM and have prognostic and predictive value.

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Section: Prognostic Molecular Markers In Gbmmentioning

confidence: 99%

Epidemiologic and Molecular Prognostic Review of Glioblastoma

Thakkar

Dolecek

Horbinski

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

995

776

View full text Add to dashboard Cite

show abstract

“…Activated EGFR can form the Grb2/SOS complex to activate the p21 RAS pathway and MAPK/ERK-AP-1 activation (11). EGFR is amplified or mutated in approximately 60% of primary GBM tumors (12). About 40% to 60% of GBMs show constitutive activation of mutant EGFR (EGFRvIII), resulting in poor clinical prognosis (13).…”

Section: Introductionmentioning

confidence: 99%

Temozolomide Induces the Production of Epidermal Growth Factor to Regulate MDR1 Expression in Glioblastoma Cells

Munoz

Rodriguez-Cruz

Greco

et al. 2014

Molecular Cancer Therapeutics

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Glioblastoma multiforme (GBM) commonly resists the frontline chemotherapy treatment temozolomide. The multidrug resistance gene (MDR1) and its protein, P-glycoprotein (P-gp), are associated with chemoresistance. This study investigated the mechanisms underlying MDR1-mediated resistance by GBM to temozolomide. P-gp trafficking was studied by flow cytometry and Western blot analysis. MDR1 expression was analyzed by real-time PCR and reporter gene assays. AP-1 interaction with MDR1 was studied by chromatin immunoprecipitation assay. EGF production was analyzed by ELISA, EGFR signaling was determined by Western blot analysis, and in vivo response to erlotinib and/or temozolomide was studied in nude mice. During the early phase of temozolomide treatment, intracellular P-gp was trafficked to the cell membrane, followed by conformational change into active P-gp. At the later phase, gene transcription of MDR1 was induced by temozolomide-mediated production of EGF. EGF activated ERK1/2-JNK-AP-1 cofactors (c-jun and c-fos). An inhibitor of EGFR kinase (erlotinib) given to nude mice with GBM prevented temozolomideinduced resistance. The results identified an essential role for activated EGFR in the resistance of GBM to temozolomide. Temozolomide resistance occurred through a biphasic response; first, by a conformational change in P-gp into the active form and, second, by releasing EGF, which caused autocrine stimulation of GBM cells to induce MDR1. Pharmacologic inhibition of EGFR kinase blunted the ability of GBM cells to resist temozolomide. These findings may explain reports on the common occurrence of mutant EGFR (EGFRvIII) and EGFR expansion in the resistance of GBM cells. Mol Cancer Ther; 13(10); 2399-411. Ó2014 AACR.

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“…To test whether this concept might hold true in specimens from patients with primary GBM, we selected the epidermal growth factor receptor (EGFR) as a prospective GBM CSC marker (14,15). EGFR expression in GBM has both diagnostic and prognostic significance (16)(17)(18)(19) and it is associated with tumor progression (20).…”

Section: Introductionmentioning

confidence: 99%

Epidermal Growth Factor Receptor Expression Identifies Functionally and Molecularly Distinct Tumor-Initiating Cells in Human Glioblastoma Multiforme and Is Required for Gliomagenesis

et al. 2010

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Epidermal growth factor receptor (EGFR) is a known diagnostic and, although controversial, prognostic marker of human glioblastoma multiforme (GBM). However, its functional role and biological significance in GBM remain elusive. Here, we show that multiple GBM cell subpopulations could be purified from the specimens of patients with GBM and from cancer stem cell (CSC) lines based on the expression of EGFR and of other putative CSC markers. All these subpopulations are molecularly and functionally distinct, are tumorigenic, and need to express EGFR to promote experimental tumorigenesis. Among them, EGFRexpressing tumor-initiating cells (TIC) display the most malignant functional and molecular phenotype. Accordingly, modulation of EGFR expression by gain-of-function and loss-of-function strategies in GBM CSC lines enhances and reduces their tumorigenic ability, respectively, suggesting that EGFR plays a fundamental role in gliomagenesis. These findings open up the possibility of new therapeutically relevant scenarios, as the presence of functionally heterogeneous EGFR pos and EGFR neg TIC subpopulations within the same tumor might affect clinical response to treatment. Cancer Res; 70(19); 7500-13. ©2010 AACR.

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Primary glioblastomas with and without EGFR amplification: Relationship to genetic alterations and clinicopathological features

Cited by 38 publications

References 22 publications

Epidemiologic and Molecular Prognostic Review of Glioblastoma

Epidemiologic and Molecular Prognostic Review of Glioblastoma

Temozolomide Induces the Production of Epidermal Growth Factor to Regulate MDR1 Expression in Glioblastoma Cells

Epidermal Growth Factor Receptor Expression Identifies Functionally and Molecularly Distinct Tumor-Initiating Cells in Human Glioblastoma Multiforme and Is Required for Gliomagenesis

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