Quantitative proteomics analysis of clear cell renal cell carcinoma for the identification of diagnostic and prognostic biomarker panels

Clear cell Renal Cell Carcinoma (ccRCC) is the third most common and most malignant urological cancer, with a 5-year survival rate of 10% for patients with advanced tumors. Despite an increasing rate of early detections, one third of the patients already show metastasis at diagnosis. Inherent and acquired resistance to chemo- and radiotherapies complicate the treatment of the disease, leaving the current treatment option primarily to surgical resection of the tumor. Biomarkers can help to monitor and to target tumor progression and growth, and to make a better prognosis on patient outcome. However, no universal biomarkers are in clinical use for ccRCC. Here, a rigorous quantitative dimethylation-based proteomics approach is described to identify biomarker panels for the diagnosis (part I) and for the stratification (part II) of ccRCC tumors, and to illuminate the driving phosphosignaling events in renal cancers (part III). The comprehensive characterization of the ccRCC global proteome and phosphoproteome revealed that the candidate marker proteins PLOD2, FERMT3, SPARC and SIPRα are overexpressed, and that diverse kinases of the groups CDK, PAK and MAPK are highly activated in the tumor tissues compared to normal adjacent tissues. The associated phosphosignaling cascades are linked to tumor growth and metastasis. Furthermore, our analysis suggested that due to interpatient heterogeneity, ccRCC tumors distinguish into two groups with distinct overall survival of patients and different enriched malignant pathways. Overall, the suggested biomarkers can serve as targets for future treatment strategies of ccRCC tumors in combination with approved therapeutics.