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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.

SUBMITTER: Macher-Goeppinger S

PROVIDER: S-EPMC5352033 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Macher-Goeppinger Stephan S Keith Martina M Endris Volker V Penzel Roland R Tagscherer Katrin E KE Pahernik Sascha S Hohenfellner Markus M Gardner Humphrey H Grüllich Carsten C Schirmacher Peter P Roth Wilfried W

Oncotarget 20170101 1

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 ...[more]

PMID: 27894094

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Project description:Tumorigenic processes are understood to be driven by epi-/genetic and genomic alterations from single point mutations to chromosomal alterations such as insertions and deletions of nucleotides up to gains and losses of large chromosomal fragments including products of chromosomal rearrangements e.g. fusion genes and proteins. Overall comparisons of copy number alterations (CNAs) presented in 48 clear cell renal cell carcinoma (ccRCC) genomes resulted in ratios of gene losses versus gene gains between 26 ccRCC Fuhrman malignancy grades G1 (ratio 1.25) and 20 G3 (ratio 0.58). Gene losses and gains of 15762 CNA genes were mapped to 795 chromosomal cytoband loci including 280 KEGG pathways. CNAs were classified according to their contribution to Fuhrman tumour gradings G1 and G3. Gene gains and losses turned out to be highly structured processes in ccRCC genomes enabling the subclassification and stratification of ccRCC tumours in a genome-wide manner. CNAs of ccRCC seem to start with common tumour related gene losses flanked by CNAs specifying Fuhrman grade G1 losses and CNA gains favouring grade G3 tumours. The appearance of recurrent CNA signatures implies the presence of causal mechanisms most likely implicated in the pathogenesis and disease-outcome of ccRCC tumours distinguishing lower from higher malignant tumours. The diagnostic quality of initial 201 genes (108 genes supporting G1 and 93 genes G3 phenotypes) has been successfully validated on published Swiss data (GSE19949) leading to a restricted CNA gene set of 171 CNA genes of which 85 genes favour Fuhrman grade G1 and 86 genes Fuhrman grade G3. Regarding these gene sets overall survival decreased with the number of G3 related gene losses plus G3 related gene gains. CNA gene sets presented define an entry to a gene-directed and pathway-related functional understanding of ongoing copy number alterations within and between individual ccRCC tumours leading to CNA genes of prognostic and predictive value.

Project description:BackgroundSLFN11 has been found to regulate the development and progression of a variety of cancers and is associated with drug therapy, while its role in clear cell renal cell carcinoma (ccRCC) remains unclear; therefore, the aim of this study was to investigate SLFN11 expression in ccRCC patients and its correlations with clinicopathological and immunological features.MethodsGene profiles of ccRCC and the clinicopathological information of patients were downloaded from the TCGA database. Microarrays from the GEO database were used as a validation set for SLFN11 expression, which was experimentally verified in renal cancer cell lines by quantitative polymerase chain reaction (qPCR); protein expression and methylation levels were obtained from the HPA database and the UALCAN database. ROC curves, Kaplan-Meier survival analysis and Cox analysis were used to assess the diagnostic and predictive value of SLFN11 in ccRCC. Protein-protein interaction (PPI) networks for SLFN11 were obtained from the STRING website, and the TISIDB and TIMER 2.0 databases were used to study the relationship between SLFN11 and immune infiltration in the tumour microenvironment (TME).ResultsSLFN11 was significantly overexpressed in ccRCC tissues and renal cancer cell lines, which may be closely related to its hypermethylation status (P < 0.001). SLFN11 was positively correlated with a highly aggressive disease state, with the ROC curve showing an AUC value of 0.910 for SLFN11 in diagnosing ccRCC, and Kaplan-Meier and Cox analyses also revealed that upregulation of SLFN11 predicted a poor prognosis for ccRCC patients (P < 0.05). In addition, enrichment analysis showed that SLFN11 was closely associated with immune-related signalling pathways, and further exploration comprehensively demonstrated strong positive correlations with tumour immune lymphocytes, immune checkpoint genes, chemokines and chemokine receptors.ConclusionOverall, our data analysis shows that SLFN11 is a strong diagnostic and prognostic biomarker for ccRCC and is also associated with immune infiltration in the TME.

Dataset Information

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

Publications

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

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