Multiple-level copy number variations in circulating cell-free DNA for prognostic prediction of hepatocellular carcinoma with radical treatments

Abstract

Background Copy number variations (CNVs) in circulating free DNA (cfDNA) are emerging as minimally invasive prognostic biomarkers for various cancers. However, little has been reported on the multiple-level analysis of cfDNA CNVs for hepatocellular carcinoma (HCC) patients with radical treatments. Methods Here, CNVs at genome-wide, chromosomal-arm and bin levels were analyzed in cfDNA from 117 HCC patients receiving radical treatments via low-coverage whole genome sequencing. Then, the relationship between cfDNA CNVs and clinical outcomes was explored. Our results showed that a concordant profile of CNVs was observed between cfDNA and tumor tissue DNA. Three genome-wide CNV indicators including tumor fraction (TFx), prediction score (P-score) and stability score (S-score) were calculated based on genome-wide cfDNA CNVs. Results Kaplan-Meier analysis showed that the patients with high TFx, P-score and S-score exhibited a significantly poorer overall survival (OS) and recurrence free survival (RFS) than those with low TFx, P-score and S-score, respectively (All P < 0.05). Furthermore, a group of high frequency cfDNA CNVs at chromosomal-arm level including loss of 4q, 17p, 19p and the gain of 8q, 1q clearly predicted prognosis of HCC patients. Finally, a bin-level risk score was constructed based on three most relevant prognostic bin regions identified by a LASSO model. Patients with high bin-score had a significantly poorer OS than those with low bin-score (P < 0.001). Conclusion Altogether, our study indicates that the multiple-level cfDNA CNVs are significantly associated with OS and RFS in HCC patients with radical treatments, suggesting that cfDNA CNVs detected by low-coverage WGS may be used as potential prognostic biomarkers of HCC patients.