MET expression and copy number status in clear-cell renal cell carcinoma: prognostic value and potential predictive marker

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.