Expression of epidermal growth factor receptor, <i>ERBB2</i> and <i>KIT</i> in adult soft tissue sarcomas

Sato, Osamu; Wada, Takuro; Kawai, Akira; Yamaguchi, Umio; Makimoto, Atsushi; Kokai, Yasuo; Yamashita, Toshihiko; Chuman, Hirokazu; Beppu, Yasuo; Tani, Yoichi; Hasegawa, Tadashi

doi:10.1002/cncr.20986

Cited by 66 publications

(73 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…5,23,24 Previous studies have indicated another potential factor in the Akt/mTOR pathway: the activation of receptor tyrosine kinases or cytokine receptors. Epidermal growth factor receptor (EGFR), 14,25,26 insulin-like growth factor-1 receptor (IGF1R), 14,27 and plateletderived growth factor receptor a (PDGFRa) 6,28,29 have been proven responsible for Akt/mTOR pathway activation in SS, and some preclinical studies have lent credence to targeting this pathway. 6,29 Clinical trials of molecular targeting drugs also have been undertaken in STS.…”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

Setsu

Kohashi

Fushimi

et al. 2013

Cancer

View full text Add to dashboard Cite

BACKGROUND:The Akt/mammalian target of rapamycin (mTOR) pathway, downstream from phosphatidylinositol 3-kinase (PI3K), mediates cell survival and proliferation. Although this pathway reportedly contributes to the progression of synovial sarcoma, its prognostic impact has not been clarified. METHODS: The authors analyzed clinicopathologic data and phosphorylation status of Akt (a serine/threonine kinase also known as protein kinase B), mTOR, the eukaryotic translation initiation factor 4E binding protein (4E-BP1), and the S6 ribosomal protein by immunohistochemical analysis of 120 formalin-fixed, paraffin-embedded samples and by Western blot analysis of 24 frozen samples from 112 patients with synovial sarcoma. RESULTS: Akt, mTOR, 4E-BP1, and S6 were activated in 76.5%, 67.6%, 59.6%, and 42.6% of samples, respectively. Immunohistochemically positive phosphorylated (p) mTOR (pmTOR) and p4E-BP1 results were correlated with higher mitotic activity, and positive p4E-BP1 results were correlated with greater necrosis. No mutations around the hot spots in the PI3K catalytic subunit a (PI3KCA) and Akt1 genes were observed. In multivariate analysis of clinicopathologic parameters, frequent mitosis was a risk factor for shorter overall survival; and male sex, visceral location, larger tumor size, and frequent mitosis were identified as risk factors for shorter event-free survival. Positive pmTOR and p4E-BP1 results were correlated significantly with shorter overall survival, and positive p4E-BP1 results were correlated with shorter event-free survival in univariate analysis. Positive pAkt results were associated significantly with shorter event-free survival in multivariate analysis. CONCLUSIONS: In this study, the Akt/mTOR pathway was activated and was associated with worse clinical and pathologic behavior in patients with synovial sarcoma. The authors propose that this pathway may have potential as a therapeutic target.

show abstract

Section: Discussionmentioning

confidence: 99%

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

Setsu

Kohashi

Fushimi

et al. 2013

Cancer

View full text Add to dashboard Cite

show abstract

“…[14][15][16][17] In two recent studies of bone and soft tissue neoplasms, EGFR expression was noted in approximately 20% of malignant tumors, with no expression documented in benign lesions, suggesting that EGFR is preferentially expressed in sarcomas. 14,15 However, in general, kinase domain mutations in sarcomas are rare.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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

2010

View full text Add to dashboard Cite

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.

show abstract

“…4 There are a growing number of reports describing protein over-expression, gene amplification, and mutation of EGFR in bone and soft tissue tumors. Immunohistochemical analyses by us and others have shown the expression of EGFR in approximately 60% [5][6][7] and the EGFR phosphorylation (activation) in 27%. 7 Furthermore, point mutations in the tyrosine kinase domain, a critical determinant of Gefitinib sensitivity, were found in 13% of the cases.…”

mentioning

confidence: 89%

EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors

et al. 2009

View full text Add to dashboard Cite

Expression of epidermal growth factor receptor, ERBB2 and KIT in adult soft tissue sarcomas

Cited by 66 publications

References 39 publications

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

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

EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors

Contact Info

Product

Resources

About