Integration of plasma and tissue proteomes discovers consistent changes of cytoskeletal proteins and metabolite interconversion enzymes in early-stage ccRCC.A, Venn diagram of identified proteins in tissue and plasma datasets. Common differential proteins: Proteins with fold change above 1.5 (RCC vs. Control) in both tissue and plasma. B, the distribution of the relative dominance of no change (gray), agree (green), tissue-only (blue), plasma-only (orange), and disagree (red) proteins. Proteins were defined based on the consistency or inconsistency between the tissue and plasma datasets. Agree proteins were those with same direction of change in both tissue and plasma datasets. No change proteins, in both tissue and plasma, were not changed (within 1.5 fold change) between ccRCC and control. Tissue-only proteins varied between ccRCC and control in tissue dataset (larger than 1.5 fold), but not in plasma (within 1.5 fold). Plasma-only proteins varied in plasma (larger than 1.5 fold), but not in tissue (within 1.5 fold). Disagree genes performed opposite direction of change in tissue and plasma. C, pathway enrichment of tissue-plasma agree proteins, tissue-only proteins, and plasma-only proteins. D, proteins varied constantly in CPTAC tissue dataset, present tissue dataset, and plasma dataset. Overall, 54.5% of these “consistent proteins” were cytoskeletal proteins and metabolites interconversion enzymes (marked in red and green). E and F, casual network analysis predicted the upstream regulator, ITGAV, SERPINE1, HIF1, and DDX5, contributing to downstream protein upregulation and pathway disturbance associated with ccRCC pathology. Molecular in red boxes: upregulated proteins in present study. Molecular in green boxes: downregulated proteins in present study; molecular in orange boxes: predicted to be activated status; molecular in blue boxes: predicted to be inhibited status. G and H, GOBP (Go ontology for biological process) terms for plasma-only upregulated proteins(G) and plasma-only downregulated proteins(H). ccRCC, clear cell renal cell carcinoma; CPTAC, Clinical Proteomic Tumor Analysis Consortium.