Membranous Expression of Ectodomain Isoforms of the Epidermal Growth Factor Receptor Predicts Outcome after Chemoradiotherapy of Lymph Node–Negative Cervical Cancer

Halle, Cathinka; Lando, Malin; Svendsrud, Debbie Hege; Clancy, Trevor; Holden, Matthew T. G.; Sundfør, Kolbein; Kristensen, Gunnar B.; Holm, Ruth; Lyng, Heidi

doi:10.1158/1078-0432.ccr-11-0297

Cited by 15 publications

(17 citation statements)

References 51 publications

(53 reference statements)

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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%

“…Circulating sEGFR level have been used as prognosis and theragnosis predictive markers in the serum of patients with cervical [22], colorectal [23], ovarian and breast [24], [25], [26], [27]. The predictive value of sEGFR was also studied directly in tumor tissues from cervical or lung cancer [28], [29].…”

Section: Introductionmentioning

confidence: 99%

EGFR Soluble Isoforms and Their Transcripts Are Expressed in Meningiomas

et al. 2012

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“…These truncated soluble EGFR variants have been detected in several cancer types, and their levels, circulating as well as in tumor tissues, have been used as prognostic and predictive markers for ovarian, cervical, lung, and breast cancers [57–59]. Alternative splicing of other tyrosine kinase receptors such as the insulin, IGF-1, FGF, ERBB2, and ERBB4 receptors can also modulate the activation of their downstream signalling pathways [2, 19, 29, 36, 60–65].…”

Section: Regulation Of the Ras-mapk Pathway By Alternative Splicingmentioning

confidence: 99%

Regulation of the Ras-MAPK and PI3K-mTOR Signalling Pathways by Alternative Splicing in Cancer

Siegfried¹,

Bonomi

Ghigna

et al. 2013

International Journal of Cell Biology

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Alternative splicing is a fundamental step in regulation of gene expression of many tumor suppressors and oncogenes in cancer. Signalling through the Ras-MAPK and PI3K-mTOR pathways is misregulated and hyperactivated in most types of cancer. However, the regulation of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing is less well established. Recent studies have shown the contribution of alternative splicing regulation of these signalling pathways which can lead to cellular transformation, cancer development, and tumor maintenance. This review will discuss findings in the literature which describe new modes of regulation of components of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing. We will also describe the mechanisms by which signals from extracellular stimuli can be communicated to the splicing machinery and to specific RNA-binding proteins that ultimately control exon definition events.

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“…All four receptors are expressed in cervical cancer [8–11], and overexpression of ERBB family members and expression of alternative Egfr isoforms are associated with advanced stage cancers and more aggressive cancers [10, 12–14]. Moreover, the HPV oncoproteins have been linked to activation of Egfr.…”

Section: Introductionmentioning

confidence: 99%

Genetic variations in EGFR and ERBB4 increase susceptibility to cervical cancer

Ma¹,

Hovey²,

Zhang³

et al. 2013

Gynecologic Oncology

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Objectives Inherited genetic variability contributes to susceptibility to cervical cancer. We investigated the association of single nucleotide polymorphisms (SNPs) in the human epidermal growth factor receptor (ErbB) family with cervical cancer. Methods We used the transmission disequilibrium test (TDT) to look for excessive transmission of tag single nucleotide polymorphisms (tSNPs) in ERBB family members EGFR, ERBB2, ERBB3, and ERBB4 in a large sample of women with invasive and in situ cervical cancer and their biological parents (628 trios). The study used a discovery set of trios (244) analyzed by Ilumina GoldenGate in which SNPs reaching a P< .05 were re-tested by TaqMan in the combined set of 628. We also explored collaborative effects of different ERBB alleles. Results Based on single SNP TDT tests we identified 16 SNPs significant in the discover stage and six of 14 SNPs that could be assayed by TaqMan were significantly overtransmitted in women with cervical cancer in the combined replication set. Four SNPs were located in intron 1 of EGFR and two SNPs in intron 24 of ERBB4 The EGFR variants are located near multiple enhancers, silencers, and the previously identified functional common polymorphisms in intron 1. Conclusions Our data provide evidence for the involvement of intron 1 EGFR variants and intron 24 ERBB4 variants in modulating risk for the development of in situ and invasive cervical cancer. These variants should be examined in additional populations and functional studies would be needed to confirm this hypothesis.

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Membranous Expression of Ectodomain Isoforms of the Epidermal Growth Factor Receptor Predicts Outcome after Chemoradiotherapy of Lymph Node–Negative Cervical Cancer

Cited by 15 publications

References 51 publications

EGFR Soluble Isoforms and Their Transcripts Are Expressed in Meningiomas

EGFR Soluble Isoforms and Their Transcripts Are Expressed in Meningiomas

Regulation of the Ras-MAPK and PI3K-mTOR Signalling Pathways by Alternative Splicing in Cancer

Genetic variations in EGFR and ERBB4 increase susceptibility to cervical cancer

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