Non-canonical small noncoding RNAs in the plasma extracellular vesicles as novel biomarkers in gastric cancer

Identifying robust diagnostic biomarkers for gastric cancer (GC) remains a significant challenge. Emerging studies highlight extracellular vesicle (EV)-derived RNAs in cancer biology, but the diagnostic potential of circulating EV-derived small non-coding RNAs (sncRNAs) in GC is poorly understood. Using panoramic RNA display by overcoming RNA modification aborted sequencing (PANDORA-seq), we mapped non-canonical sncRNAs-specifically ribosomal RNA-derived small RNAs (rsRNAs) and transfer RNA-derived small RNAs (tsRNAs)-in plasma EVs. We identified a three-rs/tsRNA signature that discriminates GC patients from healthy individuals with high sensitivity (80.42%) and specificity (87.43%) (143 GC vs 167 controls). For early-stage GC (stage I), sensitivity and specificity were 81.97% and 81.44%, respectively. Furthermore, the three-rs/tsRNA signature was evaluated in two independent cohorts, resulting in AUC values of 0.97 and 0.91 for distinguishing GC from healthy controls. Functional analyses revealed that these rs/tsRNAs regulate the ErbB/Hippo pathways, suggesting them in the underlying pathogenesis and therapeutic potential. This study establishes a novel EV-derived sncRNA signature for early GC detection.