Increased Epidermal Growth Factor Receptor Gene Copy Number Is Associated With Poor Prognosis in Head and Neck Squamous Cell Carcinomas

Chung, Christine H.; Ely, Kim; McGavran, Loris; Varella‐Garcia, Marileila; Parker, Joel S.; Parker, N; Jarrett, Carolyn; Carter, Jesse; Murphy, Barbara A.; Netterville, James L.; Burkey, Brian B.; Sinard, Robert J.; Cmelak, Anthony J.; Levy, Shawn; Yarbrough, Wendell G.; Slebos, Robbert J.C.; Hirsch, Fred R.

doi:10.1200/jco.2006.07.2587

Cited by 530 publications

(397 citation statements)

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“…The expression levels of EGFR have been correlated with the pathogenesis of a broad range of human cancers [34]. EGFR overexpression has been found to be a marker of poor prognosis [35,36]. In the current study, we examined the effect of EGF on granulosa cell growth.…”

Section: Discussionmentioning

confidence: 99%

“…EGFR has also been shown to be highly expressed in numerous types of human cancers. Therefore, the level of EGFR expression can act as a strong prognostic factor [35,36]. EGF is a critical regulator of cell survival responses and downstream signaling events leading to cell survival, thus making it an attractive target for disease therapy [37,40].…”

Section: Discussionmentioning

confidence: 99%

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Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells

Huang

Cheng

Nishi³

et al. 2010

Reprod Biol Endocrinol

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BackgroundHomeobox (HOX) genes encode transcription factors, which regulate cell proliferation, differentiation, adhesion, and migration. The deregulation of HOX genes is frequently associated with human reproductive system disorders. However, knowledge regarding the role of HOX genes in human granulosa cells is limited.MethodsTo determine the role of HOXA7 in the regulation and associated mechanisms of cell proliferation in human granulosa cells, HOXA7 and epidermal growth factor receptor (EGFR) expressions were examined in primary granulosa cells (hGCs), an immortalized human granulosa cell line, SVOG, and a granulosa tumor cell line, KGN, by real-time PCR and Western blotting. To manipulate the expression of HOXA7, the HOXA7 specific siRNA was used to knockdown HOXA7 in KGN. Conversely, HOXA7 was overexpressed in SVOG by transfection with the pcDNA3.1-HOAX7 vector. Cell proliferation was measured by the MTT assay.ResultsOur results show that HOXA7 and EGFR were overexpressed in KGN cells compared to hGCs and SVOG cells. Knockdown of HOXA7 in KGN cells significantly decreased cell proliferation and EGFR expression. Overexpression of HOXA7 in SVOG cells significantly promoted cell growth and EGFR expression. Moreover, the EGF-induced KGN proliferation was abrogated, and the activation of downstream signaling was diminished when HOXA7 was knocked down. Overexpression of HOXA7 in SVOG cells had an opposite effect.ConclusionsOur present study reveals a novel mechanistic role for HOXA7 in modulating granulosa cell proliferation via the regulation of EGFR. This finding contributes to the knowledge of the pro-proliferation effect of HOXA7 in granulosa cell growth and differentiation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells

Huang

Cheng

Nishi³

et al. 2010

Reprod Biol Endocrinol

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“…[8][9][10] Previous studies have shown that mutations in the tyrosine kinase domain of EGFR (corresponding to exons [18][19][20][21] or amplification of the EGFR gene can be used as biomarkers for response to EGFR-targeted therapy or overall survival. 11,12 Interestingly, recent evidence suggests that EGFR expression is not unique to carcinomas but may be present in malignant bone and soft tissue tumors, with a small subset showing aberrant EGFR gene copy number and/or mutations in the tyrosine kinase domain. [13][14][15][16][17][18] However, the expression, amplification and mutation status of epithelioid sarcoma remains to be characterized.…”

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confidence: 99%

Epithelioid sarcoma expresses epidermal growth factor receptor but gene amplification and kinase domain mutations are rare

2010

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Epithelioid sarcoma is a rare, malignant, soft tissue neoplasm that can be classified into proximal, distal and fibroma-like subtypes. Regardless of subtype, epithelioid sarcoma often shows morphologic and immunophenotypic evidence of epithelial differentiation. Current therapeutic strategies include surgical resection, amputation, radiation or chemotherapy, although the overall prognosis remains poor. The epidermal growth factor receptor (EGFR) is a novel therapeutic target in carcinomas. In some carcinomas, EGFR kinase domain mutations or gene amplification may correlate with response to specific inhibitors. EGFR expression has been reported in some sarcoma types, but expression, amplification and mutations have not been studied in epithelioid sarcoma. We evaluated 15 cases of epithelioid sarcoma from 14 patients for EGFR expression using immunohistochemistry, EGFR copy number aberration using fluorescence in situ hybridization and screened for mutations in the tyrosine kinase domain of the EGFR gene using direct sequencing. In all, 14 of the 15 epithelioid sarcomas (93%) showed expression of EGFR by immunohistochemistry. A majority of the cases (n ¼ 11, 73%) showed strong (2 þ to 3 þ ) and homogeneous (475% of cells) membrane staining. No amplification or polysomy of the EGFR gene or mutations of the tyrosine kinase domain of EGFR (exons 18-21) were detected. These results imply that although EGFR is expressed in most epithelioid sarcomas regardless of subtype, gene amplification and activating mutations in the tyrosine kinase domain appear to be rare or absent. Thus, the benefit of targeted therapy against EGFR in patients with epithelioid sarcoma remains to be determined.

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“…Activation of the EGFR signaling pathway has been linked with increased cell proliferation, angiogenesis, metastasis and decreased apoptosis. The literature has presented many reports that demonstrate the link between EGFR and some types of cancer, [15][16][17][18][19][20] which are generally associated with poor clinical outcome. Small molecules that inhibit the tyrosine kinase domain of EGFR have become critical new weapons in the treatment of some tumors, including non-small-cell lung carcinomas, 21 and they include gefitinib (Iressa, Astra Zeneca) and erlotinib (Tarceva, OSI Pharmaceuticals).…”

Section: Egfr In Gastrointestinal Stromal Tumormentioning

confidence: 99%

EGFR and gastrointestinal stromal tumor: an immunohistochemical and FISH study of 82 cases

Lopes

Bacchi

2007

Modern Pathology

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Gastrointestinal stromal tumor is the most common mesenchymal neoplasm of the gastrointestinal tract. Mutually exclusive KIT or platelet-derived growth factor receptor-a mutations are key events in gastrointestinal stromal tumor pathogenesis, and specific treatment targeting KIT/platelet-derived growth factor receptor-a activation is available. Epidermal growth factor receptor plays an important role in cancer biology and also constitutes a promising molecular target of therapy. Very few reports have been published in the literature about the relationship between gastrointestinal stromal tumor and epidermal growth factor receptor. The aim of this study was to investigate epidermal growth factor receptor immunohistochemical expression and epidermal growth factor receptor gene amplification in 82 consecutive gastrointestinal stromal tumor cases using tissue microarray technique. Hematoxylin-and eosin-stained sections and clinical information were reviewed, and expression of CD117 (KIT), CD34 and epidermal growth factor receptor was investigated by immunohistochemistry. Epidermal growth factor receptor gene copy number was determined using fluorescence in situ hybridization. Immunohistochemistry revealed that CD117 and CD34 were expressed in 96 and 57% of tumors, respectively. Variable epidermal growth factor receptor protein immunohistochemical overexpression was detected in 96% of gastrointestinal stromal tumor cases, but none of the 75 cases with represented tumor tissue cores and countable fluorescence signals exhibited epidermal growth factor receptor gene amplification by fluorescence in situ hybridization. These results show that there is no correlation between epidermal growth factor receptor protein overexpression by immunohistochemistry and epidermal growth factor receptor gene amplification by fluorescence in situ hybridization. Considering that the mechanisms of epidermal growth factor receptor protein overexpression are not well understood and the possibility that anti-epidermal growth factor receptor therapy may be beneficial for patients with gastrointestinal stromal tumor that overexpresses epidermal growth factor receptor, additional studies are encouraged. Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal (GI) tract. GIST generally occurs in older individuals (over the age of 50) and it can arise anywhere along the GI tract or even outside of it (extra-GI GIST), as in mesentery, omentum, retroperitoneum and pelvis. GISTs show peculiar immunohistochemical (KIT or CD117 and CD34 positivity) and molecular genetic findings, the latter characterized by mutually exclusive KIT or plateletderived growth factor receptor-a (PDGFRA) mutations. 1,2 The KIT and PDGFRA genes encode for similarly named transmembrane tyrosine kinase receptors that are involved in the development and maintenance of several cells. Activating (gain-offunction) mutations of KIT or PDGFRA permit the phosphorylation of the receptor tyrosine kinases, with activation of intracellular do...

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Increased Epidermal Growth Factor Receptor Gene Copy Number Is Associated With Poor Prognosis in Head and Neck Squamous Cell Carcinomas

Abstract: High EGFR gene copy number by FISH is frequent in HNSCC and is a poor prognostic indicator. Additional investigation is indicated to determine the biologic significance and implications for EGFR inhibitor therapies in HNSCC.

Cited by 530 publications

References 40 publications

Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells

Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells

Epithelioid sarcoma expresses epidermal growth factor receptor but gene amplification and kinase domain mutations are rare

EGFR and gastrointestinal stromal tumor: an immunohistochemical and FISH study of 82 cases

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