Decoding the Plasma Proteomic Landscape of Clear Cell Renal Cell Carcinoma Reveals Diagnostic and Prognostic Liquid Biopsy Biomarkers

Clear cell renal cell carcinoma (ccRCC) remains the most lethal urological malignancy, with high metastatic rates, both at initial diagnosis and during disease progression, contributing to poor survival outcomes. Current diagnostic and prognostic approaches rely primarily on histopathology, limiting early detection of localized disease and relevant intervention for metastatic patients. Here, we performed the most extensive to-date mass spectrometry-based discovery profiling of longitudinal plasma samples collected across multiple clinical follow-up points spanning up to five years post-diagnosis., to characterize the circulating plasma proteome and identify biomarkers for localized and metastatic disease. Network analysis identified protein modules enriched in pathways involved in matrix remodeling and metabolic deregulation, perpetuating the ccRCC phenotype. A five-protein signature, comprising PRL, THBS1, ANGPT1, IGFBP1, and SRGN, demonstrated high diagnostic performance for localized ccRCC. Notably, PRL appeared as a promising stand-alone biomarker (AUC = 0.812), with independent validation confirming its utility as a diagnostic biomarker. Importantly, a six-protein signature (AMBP, C1S, C2, IGFBP3, RASGRP2, TFRC) stringently distinguished metastatic from high-grade non-metastatic ccRCC cases. Further validation of these signatures could inform clinical decision-making, enabling early detection of metastasis and minimal residual disease and real-time longitudinal monitoring for ccRCC patients. Statement of SignificanceThis study presents the most comprehensive longitudinal plasma proteomic dataset for ccRCC to date, defining robust circulating protein biomarker signatures for both localized and metastatic disease, and establishing a proteomic landscape for minimally invasive, real-time monitoring and improved clinical management of ccRCC patients. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/742031v1_ufig1.gif" ALT="Figure 1000"> View larger version (35K): org.highwire.dtl.DTLVardef@16a0a0aorg.highwire.dtl.DTLVardef@b950b1org.highwire.dtl.DTLVardef@60ca2dorg.highwire.dtl.DTLVardef@7980c3_HPS_FORMAT_FIGEXP M_FIG C_FIG