title: Evaluation of tyrosine kinase receptors in brain metastases of clear cell renal cell carcinoma reveals cMet as a negative prognostic factor.
abstract: OBJECTIVE
  Brain metastases (BMs) of clear cell renal cell carcinoma (ccRCC) are associated with a dismal prognosis, with limited treatment options. Tyrosine kinases are relevant 'druggable' biomarkers. The aim of this study was to evaluate the tyrosine kinase receptors anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor-α (PDGFRA) and cMet in a large series of ccRCC BMs.
  
  
  RESULTS
  ALK, EGFR, PDGFRA and cMet protein expression was determined by immunohistochemistry in 53 ccRCCs BMs and 12 matched primary tumours. ALK and MET gene status and copy number alterations of chromosome 7 were studied with fluorescence in-situ hybridization (FISH). Data on the expression of hypoxia-inducible factor 1α (HIF1α) and Ki67 and microvessel density were available from previous studies. ALK was negative in all analysed specimens. EGFR was overexpressed in 41 of 51 (80.4%) BMs and in seven of eight primary tumours, PDGFRA was overexpressed in all BMs except one and in all primary tumours, and cMet was expressed in 26 of 50 (52%) BMs and in two of seven primary tumours, and did not correlate with MET amplification or polysomy 7. cMet was the only parameter associated with significantly shorter BM-specific survival (median 8 months versus 33 months, P = 0.005, Cox regression).
  
  
  CONCLUSIONS
  EGFR, PDGFRA and cMet are commonly overexpressed in ccRCC BMs. cMet overexpression correlates with significantly shorter BM-specific survival.
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Ana-Iris
authors.initials: AI
authors.lastname: Schiefer
authors.affiliation: Pathology Überlingen, Überlingen, Germany.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Mesteri
authors.affiliation: Department of Internal Medicine I, Division of Oncology & Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Berghoff
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Haitel
authors.affiliation: Department of Internal Medicine I, Division of Oncology & Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Manuela
authors.initials: M
authors.lastname: Schmidinger
authors.affiliation: Department of Internal Medicine I, Division of Oncology & Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Preusser
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Birner
mesh_terms: D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D015996:Survival Rate
chemical_list: C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: ALK; EGFR; PDGFRA; cMet; clear cell renal cell carcinoma