Somatic copy number alterations in circulating cell-free DNA as a predictive biomarker for hepatocellular carcinoma: insights from a proof-of-concept study

Abstract

Background and Aims

Despite improvements in hepatocellular carcinoma (HCC) management, its prognosis remains poor. Diagnosis at advanced stages often precludes curative treatment options, and currently available biomarkers (e.g., alpha-fetoprotein (AFP)) offer limited utility in early diagnosis and prognostic stratification. Liquid biopsy has emerged as a promising tool for early HCC detection and prognostic evaluation, and the analysis of circulating cell-free DNA (ccfDNA) hold significant potential as a diagnostic tool. This proof-of-concept study aimed to investigate the potential role of tumor fraction (TF) within ccfDNA as a biomarker in HCC patients.

Method

A total of 60 patients were recruited, including 13 with chronic liver disease (CLD), 24 with cirrhosis, and 23 with HCC. Plasma samples were collected, and ccfDNA was extracted for genomic analysis. TF was calculated by focusing on somatic copy number alterations (SCNAs) within the ccfDNA.

Results

In patients with CLD and cirrhosis (n = 37), circulating tumor DNA (ctDNA) was undetectable with the exception of one cirrhotic patient, who presented a significant TF (17 %) and displayed HCC shortly after. Conversely, 5 out of 22 HCC patients (21.7 %) exhibited detectable ctDNA, with TF levels ranging from 3.0 % to 32.6 %. Patients with higher TF levels were characterized by more aggressive disease features, including elevated AFP levels, larger tumor sizes, multiple tumor nodules, and advanced-stage disease.

Conclusion

Preliminary evidence from this study suggests that the analysis of TF, specifically through the detection of SCNAs, could serve as a promising non-invasive tool for the identification and evaluation of HCC. The innovative approach has the potential to significantly enhance early diagnosis and may also improve prognostic stratification in HCC patients.