Adult diffuse gliomas produce mRNA transcripts encoding EGFR isoforms lacking a tyrosine kinase domain

Guillaudeau, Angélique; Durand, Karine; Rabinovitch-Chable, Hélène; Pommepuy, Isabelle; Mesturoux, Laura; Robert, Sandrine; Chaunavel, Alain; Moreau, Jean-Jacques; Labrousse, François

doi:10.3892/ijo.2011.1287

Cited by 18 publications

(19 citation statements)

References 38 publications

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“…Indeed, others and we reported strong difference in immunohistochemical labeling according to the EGFR domain, ECD or ICD, targeted by primary antibodies [5], [28], [30].…”

Section: Introductionmentioning

confidence: 67%

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EGFR Soluble Isoforms and Their Transcripts Are Expressed in Meningiomas

et al. 2012

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The EGFR (epidermal growth factor receptor) is involved in the oncogenesis of many tumors. In addition to the full-length EGFR (isoform a), normal and tumor cells produce soluble EGFR isoforms (sEGFR) that lack the intracellular domain. sEGFR isoforms b, c and d are encoded by EGFR variants 2 (v2), 3 (v3) and 4 (v4) mRNA resulting from gene alternative splicing. Accordingly, the results of EGFR protein expression analysis depend on the domain targeted by the antibodies. In meningiomas, EGFR expression investigations mainly focused on EGFR isoform a. sEGFR and EGFRvIII mutant, that encodes a constitutively active truncated receptor, have not been studied. In a 69 meningiomas series, protein expression was analyzed by immunohistochemistry using extracellular domain targeted antibody (ECD-Ab) and intracellular domain targeted antibody (ICD-Ab). EGFRv1 to v4 and EGFRvIII mRNAs were quantified by RT-PCR and EGFR amplification revealed by MLPA. Results were analyzed with respect to clinical data, tumor resection (Simpson grade), histological type, tumor grade, and patient outcome.Immunochemical staining was stronger with ECD-Ab than with ICD-Ab. Meningiomas expressed EGFRv1 to -v4 mRNAs but not EGFRvIII mutant. Intermediate or high ECD-Ab staining and high EGFRv1 to v4 mRNA levels were associated to a better progression free survival (PFS). PFS was also improved in women, when tumor resection was evaluated as Simpson 1 or 2, in grade I vs. grade II and III meningiomas and when Ki67 labeling index was lower than 10%.Our results suggest that, EGFR protein isoforms without ICD and their corresponding mRNA variants are expressed in meningiomas in addition to the whole isoform a. EGFRvIII was not expressed. High expression levels seem to be related to a better prognosis. These results indicate that the oncogenetic mechanisms involving the EGFR pathway in meningiomas could be different from other tumor types.

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“…Indeed, others and we reported strong difference in immunohistochemical labeling according to the EGFR domain, ECD or ICD, targeted by primary antibodies [5], [28], [30].…”

Section: Introductionmentioning

confidence: 67%

“…Primers sequence and locations were carefully selected to amplify EGFRv1-vIII, EGFRv2, EGFRv3, EGFRv4, EGFRvIII and hypoxanthine phosphoribosyl transferase (HPRT) as previously described [5]. For quantitative PCR of v1, v2, v3, v4 transcripts, HPRT was used to normalize results, based on previous comparative experiments.…”

Section: Methodsmentioning

confidence: 99%

EGFR Soluble Isoforms and Their Transcripts Are Expressed in Meningiomas

et al. 2012

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“…In the case of VEGFR, one intron retention leads to the production of a shorter and decoy receptor that is dominant negative (Kendall et al, 1996 ; Vorlová et al, 2011 ). Similarly, alternative splicing in EGFR pre-mRNA produces several isoforms, some of which are dominant negative whereas others are constitutively active, leading to enhanced tumorgenicity, migration and invasion (Guillaudeau et al, 2012a , b ; Piccione et al, 2012 ; Zhou M. et al, 2013 ; Zhou Z. J. et al, 2013 ; Padfield et al, 2015 ).…”

Section: Changes In Upstream Signaling Pathways That Deregulate Splicmentioning

confidence: 99%

The Cancer Spliceome: Reprograming of Alternative Splicing in Cancer

Younis

2018

Front. Mol. Biosci.

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Alternative splicing allows for the expression of multiple RNA and protein isoforms from one gene, making it a major contributor to transcriptome and proteome diversification in eukaryotes. Advances in next generation sequencing technologies and genome-wide analyses have recently underscored the fact that the vast majority of multi-exon genes under normal physiology engage in alternative splicing in tissue-specific and developmental-specific manner. On the other hand, cancer cells exhibit remarkable transcriptome alterations partly by adopting cancer-specific splicing isoforms. These isoforms and their encoded proteins are not insignificant byproducts of the abnormal physiology of cancer cells, but either drivers of cancer progression or small but significant contributors to specific cancer hallmarks. Thus, it is paramount that the pathways that regulate alternative splicing in cancer, including the splicing factors that bind to pre-mRNAs and modulate spliceosome recruitment. In this review, we present a few distinct cases of alternative splicing in cancer, with an emphasis on their regulation as well as their contribution to cancer cell phenotype. Several categories of splicing aberrations are highlighted, including alterations in cancer-related genes that directly affect their pre-mRNA splicing, mutations in genes encoding splicing factors or core spliceosomal subunits, and the seemingly mutation-free disruptions in the balance of the expression of RNA-binding proteins, including components of both the major (U2-dependent) and minor (U12-dependent) spliceosomes. Given that the latter two classes cause global alterations in splicing that affect a wide range of genes, it remains a challenge to identify the ones that contribute to cancer progression. These challenges necessitate a systematic approach to decipher these aberrations and their impact on cancer. Ultimately, a sufficient understanding of splicing deregulation in cancer is predicted to pave the way for novel and innovative RNA-based therapies.

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“…Some antibodies recognize the extracellular domain of the receptor, whereas others recognize the intracellular domain and this affects the results, 37,38 especially in glioma where different isoforms of EGFR may be expressed. 39 In our study, we used an antibody directed against the extracellular domain of EGFR. Guillaudeau et al 39 showed that antibodies recognizing the extracellular domain of EGFR were more sensitive for the detection of EGFR expression.…”

Section: Discussionmentioning

confidence: 99%

“…39 In our study, we used an antibody directed against the extracellular domain of EGFR. Guillaudeau et al 39 showed that antibodies recognizing the extracellular domain of EGFR were more sensitive for the detection of EGFR expression. This could explain why we found EGFR expression in nearly all IG.…”

Section: Discussionmentioning

confidence: 99%

Cells with intense EGFR staining and a high nuclear to cytoplasmic ratio are specific for infiltrative glioma: a useful marker in neuropathological practice

et al. 2013

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Background. The differential diagnosis between infiltrative glioma (IG) and benign or curable glial lesions, such as gliosis, pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor, ganglioglioma, or demyelinating disease, may be challenging for the pathologist because specific markers are lacking. Recently, we described a strong EGFR immunolabelling pattern in cells with a high nuclear to cytoplasmic ratio that enables the discrimination of low-grade IG from gliosis. The aim of this study was to extend our observation to high-grade glioma to assess whether EGFR expression pattern is of value in the discrimination of all IG from noninfiltrative glial lesions (NIG), including gliosis, benign tumors, and demyelinating disease. Methods. One hundred one IG and 58 NIG were compared for immunohistochemical expression of EGFR with use of an antibody that recognizes an epitope in the extracellular domain of both EGFRwt and EGFRvIII. Highly EGFR-positive cells with a high nuclear to cytoplasmic ratio were isolated and further characterized. Results. Cells with intense EGFR staining and a high nuclear to cytoplasmic ratio were significantly associated with the diagnosis of IG (P , .0001). The sensitivity and specificity of this staining pattern for the diagnosis of IG were 95% and 100%, respectively. EGFR expression was independent of IDH1 mutations and EGFR amplification. Finally, we showed that these particular cells displayed the phenotype and properties of glial progenitors and coexpressed CXCR4, a marker of invasiveness. Conclusions. We demonstrate that cells with intense EGFR staining and a high nuclear to cytoplasmic ratio are specific criteria for the diagnosis of IG, irrespective of grade, histological subtype, and progression pathway, and their identification represents a tool to discriminate IG from benign or curable glial lesions. 5 It is therefore very important for pathologists to develop histological markers to identify infiltrating glioma cells. To date, no ideal marker has been identified for this purpose. In practice, the most useful markers are MIB1/Ki67 6,7 and p53, 8,9 but these lack sensitivity and specificity. 10 More recently, the mutated R132H form of isocitrate dehydrogenase 1 (IDH1), which can be specifically detected by immunohistochemistry, 11,12 has been shown to be a good marker of grade II and grade III gliomas and of secondary glioblastomas.13 -15 However IDH1 (R132H) is rare in primary glioblastomas 16 and is not useful for the diagnosis of this subtype, which represents the most common IG. A marker specific for infiltrating cells, which are characteristic of IG regardless of grade or histological subtype, would be of value.Recently, we showed that the EGFR immunolabelling pattern can discriminate low-grade glioma from gliosis. 17The criterion that characterized low-grade gliomas was strong EGFR immunostaining in cells with a high nuclear to cytoplasmic ratio. EGFR overexpression is frequent in gliomas. In 40% of glioblastomas, EGFR overexpression is secondary to gene amplification...

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Adult diffuse gliomas produce mRNA transcripts encoding EGFR isoforms lacking a tyrosine kinase domain

Cited by 18 publications

References 38 publications

EGFR Soluble Isoforms and Their Transcripts Are Expressed in Meningiomas

EGFR Soluble Isoforms and Their Transcripts Are Expressed in Meningiomas

The Cancer Spliceome: Reprograming of Alternative Splicing in Cancer

Cells with intense EGFR staining and a high nuclear to cytoplasmic ratio are specific for infiltrative glioma: a useful marker in neuropathological practice

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