RNA gene expression-based liquid biopsies for diagnosing hepatocellular carcinoma

The incidence of non-alcoholic steatohepatitis, a significant risk factor for hepatocellular carcinoma (HCC), is on the rise, highlighting the urgent need for improved diagnostic biomarkers. To date, no systematic analysis has evaluated international studies using liquid samples to assess the utilization of RNA species as biomarkers for HCC. Liquid biopsies based on RNA expression offer more specific and sensitive diagnostic biomarkers for HCC than alpha-fetoprotein (AFP). The inclusion criteria mandated English-language articles, freely available full texts, and primary research published between January 1, 2019, and May 15, 2024. Quantitative analysis was performed using the area under the receiver operating characteristic (ROC) curve values, while qualitative analysis assessed study populations, sample sizes, and levels of evidence. A total of 19 studies were ultimately included in the review. The results indicated that liquid biopsies yielded biomarkers with higher area under the ROC curve values compared to AFP. Current studies have demonstrated, although with limitations, that RNA expression techniques can yield sensitive and specific diagnostic biomarkers. Among the evaluated studies, P-element-induced wimpy testis (PIWI) transcripts exhibited the highest potential as diagnostic biomarkers. However, key limitations include heterogeneity among the studies and inadequate level one evidence. Consequently, future randomized controlled trials should focus on validating the diagnostic utility of PIWI transcripts in a more targeted and standardized manner.