Early detection of hepatocellular carcinoma via liquid biopsy: panel of small extracellular vesicle‐derived long noncoding RNAs identified as markers

This study investigated the diagnostic potential of serum small extracellular vesicle‐derived long noncoding RNAs (EV‐lncRNAs) for hepatocellular carcinoma (HCC). Driver oncogenic lncRNA candidates were selected by a comparative analysis of lncRNA expression profiles from two whole transcriptome human HCC datasets (Catholic_LIHC and TCGA_LIHC). Expression of selected lncRNAs in serum and small EVs was evaluated using quantitative reverse transcription PCR. Diagnostic power of serum EV‐lncRNAs for HCC was determined in the test (n = 44) and validation (n = 139) cohorts. Of the six promising driver onco‐lncRNAs, DLEU2, HOTTIP, MALAT1, and SNHG1 exhibited favorable performance in the test cohort. In the validation cohort, serum EV‐MALAT1 displayed excellent discriminant ability, while EV‐DLEU2, EV‐HOTTIP, and EV‐SNHG1 showed good discriminant ability between HCC and non‐HCC. Furthermore, a panel combining EV‐MALAT1 and EV‐SNHG1 achieved the best area under the curve (AUC; 0.899, 95% CI = 0.816–0.982) for very early HCC, whereas a panel with EV‐DLEU2 and alpha‐fetoprotein exhibited the best positivity (96%) in very early HCC. Serum small EV‐MALAT1, EV‐DLEU2, EV‐HOTTIP, and EV‐SNHG1 may represent promising diagnostic markers for very early‐stage HCC. The present study investigates the diagnostic potential of serum small extracellular vesicle‐derived long noncoding RNAs (EV‐lncRNAs) for the early detection of hepatocellular carcinoma (HCC). We investigated driver lncRNA candidates by a comparative analysis of lncRNA expression profiles and identified that panels of four serum EV‐lncRNAs, EV‐MALAT1, EV‐DLEU2, EV‐HOTTIP, and EV‐SNHG1, with or without AFP, showed high positivity rates (86–96%) in very early‐stage HCC, thus highlighting their potential as promising diagnostic liquid biopsy markers.