Multifaceted dysregulation of the epidermal growth factor receptor pathway in clear cell sarcoma of the kidney.
Date
2007-08Author
Little, SE
Bax, DA
Rodriguez-Pinilla, M
Natrajan, R
Messahel, B
Pritchard-Jones, K
Vujanic, GM
Reis-Filho, JS
Jones, C
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
Humans
Nephroma, Mesoblastic
Rhabdoid Tumor
Sarcoma, Clear Cell
Kidney Neoplasms
Immunoenzyme Techniques
Tissue Array Analysis
In Situ Hybridization
Signal Transduction
Gene Amplification
Phosphorylation
Mutation
Child, Preschool
Infant
Wilms Tumor
Proto-Oncogene Proteins c-akt
PTEN Phosphohydrolase
ErbB Receptors
Research team
Functional Genomics
Glioma Team
Language
eng
License start date
2007-08
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2007, 13 (15 Pt 1), pp. 4360 - 4364