Voldborg BR, Damstrup L, Spang-Thomsen M, Poulsen HSEpidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann Oncol 8: 1197-1206

Section for Radiation Biology, Finsen Centre, Rigshospitalet, Copenhagen, Denmark.
Annals of Oncology (Impact Factor: 7.04). 01/1998; 8(12):1197-206. DOI: 10.1023/A:1008209720526
Source: PubMed


The epidermal growth factor receptor (EGFR) is a growth factor receptor that induces cell differentiation and proliferation upon activation through the binding of one of its ligands. The receptor is located at the cell surface, where the binding of a ligand activates a tyrosine kinase in the intracellular region of the receptor. This tyrosine kinase phosphorylates a number of intracellular substrates that activates pathways leading to cell growth, DNA synthesis and the expression of oncogenes such as fos and jun. EGFR is thought to be involved the development of cancer, as the EGFR gene is often amplified, and/or mutated in cancer cells. In this review we will focus on: (I) the structure and function of EGFR, (II) implications of receptor/ligand coexpression and EGFR mutations or overexpression, (III) its effect on cancer cells, (IV) the development of the malignant phenotype and (V) the clinical aspects of therapeutic targeting of EGFR.

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Available from: Bjørn Voldborg, Mar 18, 2014
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    • "All these transmembrane receptors contain intrinsic kinase activities and are activated by modified tyrosine residues. It is believed that the aberrant activation of the signaling pathway contributes to tumorigenic events, including increased cellular proliferation, prevention of apoptosis, tumor cell invasion and metastasis (6). In numerous studies, it has been shown that the EGFR status is an independent prognostic factor in various tumor types (7). "
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    ABSTRACT: The expression of epidermal growth factor receptor (EGFR) has been linked to clinical outcome in several solid tumors. However, the clinical significance of EGFR (c-erbB1) in gastric cancer remains unclear. The present study was designed to detect the clinical implications of EGFR in the Turkish population. Paraffin-embedded tissue microarrays containing gastric cancer tissue were obtained from 30 patients. EGFR expression was detected using immunohistochemistry. The correlation of this biomarker to the clinicopathological features and survival of patients with gastric cancer was studied. The overall positivity rate of EGFR was 63.3%. EGFR expression was significantly correlated with an improved progression-free survival (PFS) and overall survival (OS) rate (P=0.039 and 0.01, respectively). EGFR expression is a good prognostic marker for patients with gastric cancer.
    Oncology letters 01/2014; 7(1):255-259. DOI:10.3892/ol.2013.1662 · 1.55 Impact Factor
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    • "Some, like EGFR vI (exon 1–7 deletion) and EGFR vIV (intracellular domain microdeletion), are rare [6, 9, 38, 48], while others like EGFRvII and EGFRvV are marginally more common, each accounting for more than 10 % of all GBM-associated EGFR mutations [20, 28, 32]. The vII deletion includes a small 83-amino acid stretch within the EGFR ECD [47], while EGFRvV involves a C-terminal truncation that ablates the majority of the protein’s intracellular domain, a region responsible for mediating internalization and degradation [6, 9, 48]. Functional analyses of both mutations have been complicated by their frequent co-occurrence with EGFRvIII [10]. "
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    ABSTRACT: Intragenic deletion is the most common form of activating mutation among receptor tyrosine kinases (RTK) in glioblastoma. However, these events are not detected by conventional DNA sequencing methods commonly utilized for tumor genotyping. To comprehensively assess the frequency, distribution, and expression levels of common RTK deletion mutants in glioblastoma, we analyzed RNA from a set of 192 glioblastoma samples from The Cancer Genome Atlas for the expression of EGFRvIII, EGFRvII, EGFRvV (carboxyl-terminal deletion), and PDGFRAΔ8,9. These mutations were detected in 24, 1.6, 4.7, and 1.6 % of cases, respectively. Overall, 29 % (55/189) of glioblastomas expressed at least one RTK intragenic deletion transcript in this panel. For EGFRvIII, samples were analyzed by both quantitative real-time PCR (QRT-PCR) and single mRNA molecule counting on the Nanostring nCounter platform. Nanostring proved to be highly sensitive, specific, and linear, with sensitivity comparable or exceeding that of RNA seq. We evaluated the prognostic significance and molecular correlates of RTK rearrangements. EGFRvIII was only detectable in tumors with focal amplification of the gene. Moreover, we found that EGFRvIII expression was not prognostic of poor outcome and that neither recurrent copy number alterations nor global changes in gene expression differentiate EGFRvIII-positive tumors from tumors with amplification of wild-type EGFR. The wide range of expression of mutant alleles and co-expression of multiple EGFR variants suggests that quantitative RNA-based clinical assays will be important for assessing the relative expression of intragenic deletions as therapeutic targets and/or candidate biomarkers. To this end, we demonstrate the performance of the Nanostring assay in RNA derived from routinely collected formalin-fixed paraffin-embedded tissue.
    Acta Neuropathologica 11/2013; 127(5). DOI:10.1007/s00401-013-1217-3 · 10.76 Impact Factor
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    • "EGFR is a transmembrane receptor tyrosine kinase (RTK) and is expressed in multiple cell types (Castillo et al., 2004; Soonthornthumet al., 2011). The molecular structure of EGFR comprises of an extracellular ligand binding domain, a single transmembrane section and an intracellular tyrosine kinase domain (Leahy et al., 2004), which plays an important role in cell proliferation and differentiation upon its activation (Voldborg et al., 1997; Ogiso et al., 2002). EGFR is activated when its cognate ligand epidermal growth factor (EGF) binds to its extracellular domain, which initiates homo or hetero dimerization between the members of the Erb family (Burgess et al., 2008). "
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    ABSTRACT: Background: The activation and inactivation of receptor tyrosine kinases are tightly regulated to ensure faithful replication of cells. After having transduced extracellular growth activating signals, activated EGFR is subjected to downregulation either by clathrin mediated endocytosis or c-Cbl mediated proteasome degradation depending on the ligand concentration. c-Cbl is an ubiquitin ligase which requires a phosphorylated tyrosine residue at position 1045 in the cytoplasmic domain of EGFR to interact and add ubiquitin molecules. While activating mutations in exons 19 and 21 have been associated with the development of several cancers, the status of mutations at tyrosine 1045 coding exon 27 of EGFR remain to be investigated. Consistently, defective phosphorylation at 1045 has been associated with sustained phosphorylation of EGFR in non-small lung carcinomas. Hence in the present study we investigated the genetic status of the tyrosine 1045 coding site within exon 27 of EGFR gene to explore for possible occurrence of mutations in this region, especially since no studies have addressed this issue so far. Materials and methods: Tumor chromosomal DNA isolated from thirty five surgically excised oral squamous cell carcinoma tissues was subjected to PCR amplification with intronic primers flanking the tyrosine 1045 coding exon 27 of EGFR gene. The PCR amplicons were subsequently subjected to direct sequencing to elucidate the mutation status. Results: Sequence analysis identified no mutations in the tyrosine 1045 codon of EGFR in any of the thirty five samples that were analyzed. Conclusions: The lack of identification of mutation in the tyrosine 1045 codon of EGFR suggests that mutations in this region may be relatively rare in oral squamous cell carcinomas. To the best of our knowledge, this study is the first to have explored the genetic status of exon 27 of EGFR in oral squamous cell carcinoma tissue samples.
    Asian Pacific journal of cancer prevention: APJCP 07/2013; 14(7):4279-82. DOI:10.7314/APJCP.2013.14.7.4279 · 2.51 Impact Factor
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