tRNA-Derived Fragments (tRFs) in Bladder Cancer: Increased 5′-tRF-LysCTT Results in Disease Early Progression and Patients' Poor Treatment Outcome

Simple Summary Bladder cancer (BlCa) management relies on lifelong surveillance strategies with invasive interventions that adversely affect patients' quality-of-life and lead to a high economic burden for healthcare systems. Exploitation of bladder tumors' molecular background could lead to modern precision medicine. tRNA-derived fragments (tRFs), rather than degradation debris, are novel functional small ncRNAs that have emerged as key regulators of cellular homeostasis. This is the first study of the clinical utility of tRFs in BlCa. Using in silico analysis of the TCGA-BLCA project, we identified 5 '-tRF-LysCTT (5 '-tRF of tRNA(LysCTT)) to be significantly deregulated in BlCa, and we have studied its clinical value in our cohort of 230 BlCa patients. Elevated 5 '-tRF-LysCTT levels were significantly associated with aggressive tumor phenotype as well as early disease progression and poor treatment outcome. Integration of 5 '-tRF-LysCTT with established disease markers resulted in superior prediction of patients' prognosis, supporting personalized treatment and monitoring decisions. The heterogeneity of bladder cancer (BlCa) prognosis and treatment outcome requires the elucidation of tumors' molecular background towards personalized patients' management. tRNA-derived fragments (tRFs), although originally considered as degradation debris, represent a novel class of powerful regulatory non-coding RNAs. In silico analysis of the TCGA-BLCA project highlighted 5 '-tRF-LysCTT to be significantly deregulated in bladder tumors, and 5 '-tRF-LysCTT levels were further quantified in our screening cohort of 230 BlCa patients. Recurrence and progression for non-muscle invasive (NMIBC) patients, as well as progression and patient's death for muscle-invasive (MIBC) patients, were used as clinical endpoint events. TCGA-BLCA were used as validation cohort. Bootstrap analysis was performed for internal validation and the clinical net benefit of 5 '-tRF-LysCTT on disease prognosis was assessed by decision curve analysis. Elevated 5 '-tRF-LysCTT was associated with unfavorable disease features, and significant higher risk for early progression (multivariate Cox: HR = 2.368; p = 0.033) and poor survival (multivariate Cox: HR = 2.151; p = 0.032) of NMIBC and MIBC patients, respectively. Multivariate models integrating 5 '-tRF-LysCTT with disease established markers resulted in superior risk-stratification specificity and positive prediction of patients' progression. In conclusion, increased 5 '-tRF-LysCTT levels were strongly associated with adverse disease outcome and improved BlCa patients' prognostication.