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Updated: Jul 13, 2026
Induction of Mesenchymal-Epithelial Transitions in Sarcoma Cells
Published on: April 7, 2017
Multifaceted dysregulation of the epidermal growth factor receptor pathway in clear cell sarcoma of the kidney
Suzanne E Little1, Dorine A Bax, Maria Rodriguez-Pinilla
1Paediatric Oncology, Institute of Cancer Research/Royal Marsden NHS Trust, Sutton, United Kingdom.
Purpose:
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase overexpressed in a variety of human malignancies, against which targeted therapies have shown efficacy in lung and brain tumors. Clinical responses to EGFR inhibitors have been found to be highly dependent on the presence of activating mutations, whereas gene amplification, downstream activation of Akt, and abnormalities in PTEN are also reported predictive factors. We sought to evaluate these variables in pediatric renal tumors.
Experimental Design:
We screened a series of 307 pediatric renal tumors for EGFR expression by immunohistochemistry and gene amplification by chromogenic in situ hybridization. In identifying a striking predilection for certain tumor types, we further analyzed the clear cell sarcomas of the kidney (CCSK) for mutations in EGFR and PTEN.
Results:
Although only 23 of 177 (13.0%) nonanaplastic Wilms' tumors were EGFR positive, 4 of 11 (36.4%) anaplastic tumors showed receptor overexpression. In addition, 5 of 9 (55.6%) mesoblastic nephromas and 12 of 12 (100%) CCSKs were strongly immunoreactive for EGFR. In studying the CCSKs in more detail, we identified gene amplification in 1 of 12 (8.3%) cases and a somatic T790M EGFR mutation in a further case. These two samples additionally harbored mutations in PTEN. Downstream pathway activation, as assayed by phosphorylated Akt expression, was observed in 8 of 12 (66.7%) cases.
Conclusions:
Together, these data show dysregulation of the EGFR pathway at multiple levels in CCSKs. Identification of factors predictive of poor response to targeted therapy, including the drug resistance T790M mutation, may provide a rationale for upfront trials with irreversible inhibitors of EGFR in children with these tumors.
Insights
Epidermal growth factor receptor (EGFR) pathway is dysregulated in pediatric renal tumors, particularly clear cell sarcomas of the kidney (CCSK). Identifying predictive factors like the T790M mutation may guide targeted therapy trials.
Area of Science:
- Oncology
- Molecular Biology
- Pediatric Pathology
Background:
- Epidermal growth factor receptor (EGFR) is a key target in cancer therapy, with efficacy demonstrated in lung and brain tumors.
- Clinical response to EGFR inhibitors is mutation-dependent, with gene amplification, Akt activation, and PTEN abnormalities also serving as predictive factors.
- Evaluation of these predictive factors in pediatric renal tumors is crucial for optimizing treatment strategies.
Purpose of the Study:
- To investigate the expression and alterations of the EGFR pathway in various pediatric renal tumors.
- To specifically analyze EGFR mutations, gene amplification, and PTEN abnormalities in clear cell sarcomas of the kidney (CCSK).
- To assess downstream pathway activation via phosphorylated Akt in CCSKs.
Main Methods:
- Screening of 307 pediatric renal tumors for EGFR expression using immunohistochemistry.
- Assessment of EGFR gene amplification via chromogenic in situ hybridization.
- Analysis of EGFR and PTEN mutations and phosphorylated Akt expression in CCSKs.
Main Results:
- EGFR overexpression was observed in anaplastic Wilms' tumors (36.4%), mesoblastic nephromas (55.6%), and 100% of CCSKs.
- EGFR gene amplification (8.3%) and a T790M mutation were identified in CCSKs, with concurrent PTEN mutations in these cases.
- Downstream Akt pathway activation was present in 66.7% of CCSKs.
Conclusions:
- The EGFR pathway is dysregulated at multiple levels in CCSKs.
- The presence of drug resistance mutations like T790M in CCSKs suggests potential for targeted therapy.
- These findings support the rationale for upfront clinical trials using irreversible EGFR inhibitors in pediatric patients with CCSKs.
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