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

Stephan Macher-Goeppinger,Humphrey Gardner,Martina Keith,Katrin E Tagscherer,Volker Endris,Markus Hohenfellner,Sascha Pahernik,Carsten Grüllich,Roland Penzel,Peter Schirmacher,Wilfried Roth

doi:10.18632/oncotarget.13540

Stephan Macher-Goeppinger, Humphrey Gardner + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.13540

Copy DOI

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.

Highlights

Treatment of metastatic renal cell carcinoma has dramatically changed over the last decade and multiple targeted therapies have replaced IL-2 and IFN-α immunotherapy as the primary treatment option
Despite comprehensive translational research efforts in renal cell carcinoma and availability of targeted therapy options, at present neither prognostic nor predictive biomarkers are established for routine clinical treatment stratification [28]
The rarity of cures and intrinsic or acquired resistance demands novel treatment approaches and identification of predictive and prognostic www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget biomarkers. c-Met/hepatocyte growth factor receptor (HGFR) encoded by the MET oncogene is a validated therapeutic target for a number of malignancies and results obtained from clinical trials are encouraging [30]

Summary

Introduction

Treatment of metastatic renal cell carcinoma (mRCC) has dramatically changed over the last decade and multiple targeted therapies have replaced IL-2 and IFN-α immunotherapy as the primary treatment option. These new agents, such as Sorafenib, Sunitinib or Temsirolimus, mainly target two pathways, vascular endothelial growth factor (VEGF) signaling and the mammalian target of rapamycin (mTOR) [1, 2, 3, 4, 5, 6]. Downstream signaling of HGFR includes activation of MAPK and PI3K-AKT pathway and induction of the vascular endothelial growth factor (VEGF) and in consequence evokes a variety of pleiotropic pro-tumorigenic responses, like cell migration, proliferation and angiogenesis [12]

Methods

Results

Conclusion