33 Plasma Proteomic Profiling Reveals SEZ6L2 as a Novel Biomarker in Translocation Renal Cell Carcinoma

Background Translocation renal cell carcinoma (tRCC) is a rare and aggressive kidney cancer in adults and children, which is defined by a gene fusion involving TFE3 or TFEB. Although recent molecular studies have improved the understanding of tRCC biology, non-invasive biomarkers with translational relevance remain lacking. Methods Here, we used a Proximity Extension Assay (PEA) to systematically profile 1,034 proteins across the plasma of 18 tRCC and 68 non-tRCC kidney cancer patients, uncovering SEZ6L2 as a top tRCC-specific plasma protein. Results In tRCC, SEZ6L2 plasma expression was tightly correlated with a protein signature that was enriched for cell-cycle, IL1, and Rho-GTPase signaling pathways. Notably, high expression of SEZ6L2 and its plasma signature was associated with decreased overall survival and time to treatment failure in our cohort. Conclusions This work is the most comprehensive characterization of plasma proteins in tRCC and identifies SEZ6L2 as one of the first tRCC-specific circulating biomarkers with potential for non-invasive diagnostic, monitoring, and prognostic applications.