Methylation Plus AFP for Early HCC Detection: Hepatology Communications | July 2026

Introduction:

Early detection of hepatocellular carcinoma (HCC) is critical for improving access to curative therapies, yet current surveillance with ultrasound and alpha-fetoprotein (AFP) has suboptimal sensitivity, particularly in patients with metabolic dysfunction–associated steatotic liver disease (MASLD). This study evaluated a blood-based assay combining cell-free DNA methylation profiling with AFP for the early detection of HCC in at-risk individuals.

Why was this study needed?

. Ultrasound-based HCC surveillance has limited sensitivity, especially for early-stage tumors.

. AFP alone lacks adequate diagnostic accuracy for routine surveillance.

. Blood-based biomarkers may improve surveillance adherence and early cancer detection.

. Cell-free DNA methylation represents a promising approach for detecting HCC before clinical progression.

Results:

In this multicenter validation study including prospective and archived samples from patients with HCC and at-risk controls, the combination of cell-free DNA methylation profiling and AFP demonstrated excellent diagnostic performance for HCC detection, significantly outperforming either test alone. Importantly, the combined assay maintained high accuracy for early-stage HCC within the Milan criteria, with substantially improved sensitivity while preserving high specificity. The improvement over AFP alone was consistent across major demographic groups and liver disease etiologies, highlighting the robustness of this multimarker approach for detecting early, potentially curable HCC.

Clinical Impact:

This study supports the growing role of blood-based biomarkers in HCC surveillance. Combining methylation profiling with AFP could overcome many limitations of ultrasound, particularly in patients with obesity or MASLD, where imaging quality is often suboptimal. If validated in prospective surveillance cohorts, this strategy could improve early HCC detection, increase eligibility for curative therapies, and complement or potentially enhance current surveillance algorithms.

Bottom Line:

A blood test combining cell-free DNA methylation profiling with AFP significantly improves the detection of early-stage HCC compared with either biomarker alone, representing a promising next-generation surveillance strategy for at-risk patients.