Multifaceted dysregulation of the EGFR pathway in clear cell sarcoma of the kidney Free

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EGFR is a receptor tyrosine kinase overexpressed in a variety of human malignancies, against which targetted therapies have shown efficacy in lung and brain tumors. In non small cell lung cancer, clinical responses to EGFR inhibitors have been found to be highly dependent on the presence of activating mutations, whilst gene amplification, downstream activation of Akt, and abnormalities in PTEN are also reported predictive factors. We screened a series of paediatric renal tumors for EGFR expression by immunohistochemistry, and identified a striking predilection for certain histologies. Although only 23/177 (13.0%) favorable histology Wilms tumors were EGFR positive, 4/11 (36.4%) anaplastic tumours showed receptor overexpression. In addition, 5/9 (55.6%) congenital mesoblastic nephromas and 12/12 (100%) clear cell sarcomas of the kidney (CCSKs) were strongly immunoreactive for EGFR. Studying the CCSKs in more detail, we identified gene amplification by chromogenic in situ hybridisation in 1/12 (8.3%) cases, and a somatic T790M EGFR mutation in a further case. These two samples additionally harboured mutations in PTEN. Downstream pathway activation, as assayed by immunohistochemistry for phosphorylated Akt expression, was observed in 8/12 (66.7%) cases. Together, these data demonstrate 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.