Tissue‐Derived Extracellular Vesicles Define Diagnostic Biomarkers for Renal Cell Carcinoma

Tissue-derived extracellular vesicles (Ti-EVs) play a crucial role in tumour progression, but their value as differential diagnostic markers for various renal cell carcinoma (RCC) subtypes remains uncertain. Through analysis of paired tumour and normal tissues, along with their corresponding Ti-EVs, we identified NEAT1 and MMP15 as markers for papillary RCC (pRCC); DSG2 and AC026888.1 for chromophobe RCC (chRCC); NDUFA4L2, SERPINA1, VEGFA, EGLN3, CPE and C6orf223 for low-grade clear cell RCC (low-grade ccRCC); and NDUFA4L2, APOC1, TGFBI and LINC00887 for high-grade ccRCC (high-grade ccRCC). In an external validation cohort, an area under the curve (AUC) of 0.922 for low-grade ccRCC detection and 0.874 for high-grade ccRCC detection was achieved, respectively, using urinary EVs. Furthermore, integrating single-cell sequencing data revealed that SERPINA1 and VEGFA in low-grade ccRCC, and APOC1 and TGFBI in high-grade ccRCC, were derived from tumour-associated macrophages, whereas NDUFA4L2 originated from cancer cells in both low- and high-grade ccRCC.