Seven blood biomarkers are associated with TGF-β and VHL-HIF signaling in patients with clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is an aggressive kidney cancer subtype frequently associated with poor prognosis. Most ccRCC cases are asymptomatic in early stages and symptomatic mostly in advanced stages. Furthermore, the heterogeneity of ccRCC presents a challenge to design new treatments. In this study, using proximity extension assay (PEA), we analyzed blood samples from 134 patients with ccRCC and from 111 age- and gender-matched healthy donors. We identified a panel of seven proteins (ANXA1, ESM1, FGFBP1, MDK, METAP2, SDC1, and TFPI2) that are associated with clinicopathological parameters and patient survival. These biomarkers can differentiate patients with ccRCC from the control individuals with high diagnostic sensitivity and specificity. Moreover, by studying protein expression in solid tumors from the same ccRCC patients, we revealed associations between the panel biomarkers and proteins in the TGF-β and VHL-HIF signaling pathways. We found that most tumor promoting biomarkers were positively associated with TGF-β signaling and HIF-2α, and negatively associated with pVHL and HIF-1α. We also found that most tumor suppressing biomarkers were positively associated with pVHL and HIF-1α and negatively associated with TGF-β signaling and HIF-2α. For ccRCC patients, the blood protein biomarkers that were connected to poor prognosis and TGF-β/HIF-2α signaling, as identified in this study, are potentially important assets in personalized medicine.