title: Multifaceted dysregulation of the epidermal growth factor receptor pathway in clear cell sarcoma of the kidney.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Paediatric Oncology, Institute of Cancer Research/Royal Marsden NHS Trust, Sutton, United Kingdom.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Little
authors.forename: Dorine A
authors.initials: DA
authors.lastname: Bax
authors.forename: Maria
authors.initials: M
authors.lastname: Rodriguez-Pinilla
authors.forename: Rachael
authors.initials: R
authors.lastname: Natrajan
authors.forename: Boo
authors.initials: B
authors.lastname: Messahel
authors.forename: Kathy
authors.initials: K
authors.lastname: Pritchard-Jones
authors.forename: Gordan M
authors.initials: GM
authors.lastname: Vujanic
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
mesh_terms: D002675:Child, Preschool; D066246:ErbB Receptors / Q000378:metabolism*; D005784:Gene Amplification; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D007223:Infant; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D018201:Nephroma, Mesoblastic / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018335:Rhabdoid Tumor / Q000378:metabolism / Q000473:pathology; D018227:Sarcoma, Clear Cell / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D046888:Tissue Array Analysis; D009396:Wilms Tumor / Q000378:metabolism / Q000473:pathology
chemical_list: D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human