A Cell-free tsRNA Signature for Early Detection of Hepatocellular Carcinoma

Liver cancer is a major global health challenge, ranking as the 5th leading cause of cancer-related deaths in the U.S. and 3rd worldwide, with hepatocellular carcinoma (HCC) accounting for \~75% of cases. Incidence has more than tripled since 1980, and death rates have risen by \~2% annually, highlighting the need for improved detection and treatment. Prognosis remains poor: over 50% of HCC cases are diagnosed at stage IV, with a 1-year survival below 30%, whereas early-stage HCC (stages I-II) can achieve up to 74% 5-year survival with curative interventions. Major risk factors include viral hepatitis (HBV, HCV), alcohol abuse, obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD), with non-viral HCC increasing in prevalence, particularly in Western countries. Screening programs target high-risk populations but miss many asymptomatic or average-risk individuals, contributing to late-stage diagnoses. Biomarker discovery holds promise for improving early detection. Alpha-fetoprotein (AFP), the most widely used biomarker, has limited sensitivity for early-stage HCC (39-64%). tsRNAs (tRNA-derived small RNAs) are small, single-stranded RNA molecules derived from mature or precursor tRNAs that were first detected in the urine of patients with cancer in the 1970s. Emerging noninvasive markers offer complementary advantages: cell-free tsRNAs (cf-tsRNAs) are stable and highly sensitive for detection. Integrating these biomarker types could enable robust models for accurate early HCC detection, addressing a critical gap in clinical care. This study seeks to validate a panel of more accurate and non-invasive biomarkers (cf-tsRNAs) in preoperative blood samples. Accurate early detection of HCC would help provide clear criteria for treatment decisions, such as timely surgical intervention or the addition of adjuvant chemotherapy.