title: MET expression and copy number status in clear-cell renal cell carcinoma: prognostic value and potential predictive marker.
abstract: Multiple targeted therapy for advanced clear-cell renal cell carcinoma (RCC) has substantially improved patient outcome, but complete remission is uncommon and many tumors eventually develop resistance. Mechanistic, preclinical, and early clinical data highlight c-Met / hepatocyte growth factor receptor as a promising target for RCC therapeutic agents.We have examined MET expression, frequency of MET gene copy gains and MET gene mutation in a large, hospital-based series of renal cell carcinomas with long-term follow-up information.Out of a total of 572 clear-cell RCC, only 17% were negative for MET expression whereas 32% showed high protein levels. High MET expression and MET copy number gains were associated with an aggressive phenotype and an unfavorable patient outcome. Elevated protein levels in absence of gene amplification were not attributed to mutations, based on results of targeted next-generation sequencing.Our data reveal that clear-cell RCC with MET upregulation show an aggressive behavior and MET copy number increase is evident in a substantial percentage of patients with high-grade carcinomas and metastatic disease. Diagnostic assessment of MET expression and amplification may be of predictive value to guide targeted therapy against MET signaling in patients with clear-cell RCC.
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|Molecular Tumor Pathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute of Pathology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Macher-Goeppinger
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|Molecular Tumor Pathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Keith
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Endris
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|Molecular Tumor Pathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Katrin E
authors.initials: KE
authors.lastname: Tagscherer
authors.affiliation: Department of Urology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Pahernik
authors.affiliation: Department of Urology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hohenfellner
authors.affiliation: Translational Medicine, Early Clinical Development, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
authors.forename: Humphrey
authors.initials: H
authors.lastname: Gardner
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases Heidelberg, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Grüllich
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|Molecular Tumor Pathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute of Pathology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging; D009154:Mutation; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D015996:Survival Rate; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: HGF; MET; biomarker; renal cell carcinoma; targeted therapy