Genome-wide copy number alteration and VEGFA amplification of circulating cell-free DNA as a biomarker in advanced hepatocellular carcinoma patients treated with Sorafenib

Abstract

Background Although sorafenib is the global standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC), it does not have reliable predictive or prognostic biomarkers. Circulating cell-free DNA (cfDNA) has shown promise as a biomarker for various cancers. We investigated the use of cfDNA to predict clinical outcomes in HCC patients treated with sorafenib. Methods This prospective biomarker study analyzed plasma cfDNA from 151 HCC patients who received first-line sorafenib and 14 healthy controls. The concentration and VEGFA-to-EIF2C1 ratios (the VEGFA ratio) of cfDNA were measured. Low depth whole-genome sequencing of cfDNA was used to identify genome-wide copy number alteration (CNA), and the I-score was developed to express genomic instability. The I-score was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. The primary aim of this study was to develop cfDNA biomarkers predicting treatment outcomes of sorafenib, and the primary study outcome was the association between biomarkers with treatment efficacy including disease control rate (DCR), time to progression (TTP) and overall survival (OS) in these patients. Results The cfDNA concentrations were significantly higher in HCC patients than in healthy controls (0.71 vs. 0.34 ng/μL; P < 0.0001). Patients who did not achieve disease control with sorafenib had significantly higher cfDNA levels (0.82 vs. 0.63 ng/μL; P = 0.006) and I-scores (3405 vs. 1024; P = 0.0017) than those achieving disease control. The cfDNA-high group had significantly worse TTP (2.2 vs. 4.1 months; HR = 1.71; P = 0.002) and OS (4.1 vs. 14.8 months; HR = 3.50; P < 0.0001) than the cfDNA-low group. The I-score-high group had poorer TTP (2.2 vs. 4.1 months; HR = 2.09; P < 0.0001) and OS (4.6 vs. 14.8 months; HR = 3.35; P < 0.0001). In the multivariable analyses, the cfDNA remained an independent prognostic factor for OS ( P < 0.0001), and the I-score for both TTP ( P = 0.011) and OS ( P = 0.010). The VEGFA ratio was not significantly associated with treatment outcomes. Conclusion Pretreatment cfDNA concentration and genome-wide CNA in cfDNA are potential biomarkers predicting outcomes in advanced HCC patients receiving first-line sorafenib. Electronic supplementary material The online version of this article (10.1186/s12885-019-5483-x) contains supplementary material, which is available to authorized users.

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

“…The cfDNA concentration may be in uenced by experimental operation errors in cfDNA extraction and quanti cation or by the patients' status at the time of blood extraction (26,27). And variations in cfDNA concentration have been commonly found in different laboratories (17,28). In general, all the genome-wide CNVs indicators were shown to be independent prognostic factors, exhibiting more superior e cacy to the cfDNA concentration and current evaluation variables.…”

“…Moreover, the detection of cfDNA CNVs by ultra-low coverage sequencing makes it a cost-effective approach for potential clinical applications (16). Previous studies have suggested the prognostic utility of cfDNA CNVs in HCC patients treated with Sorafenib (17). Furthermore, Cai et al have reported that plasma CNV indicator (TFx) at genomewide level are dynamically correlated with tumor burden in a relatively small cohort (n = 34) of HCC patients receiving surgical resection (18).…”

Combined use of murine double minute-2 promoter methylation and serum AFP improves diagnostic efficiency in hepatitis B virus-related hepatocellular carcinoma

“…Sorafenib is a tyrosine kinase inhibitor and has a significant therapeutic effect on advanced HCC. It has been shown that circulating cell-free DNA may be potential biomarkers for determining the effect of HCC treatment 59 . The predictive value of MDM2 methylation for the treatment outcome of sorafenib will be performed in the future study.…”

Predictive and Prognostic Factors in HCC Patients Treated with Sorafenib

“…In a recent study [35], the circulating cell free DNA (cfDNA) concentrations of VEGF were analized in HCC patients treated with sorafenib. Patients who underwent to progression disease with sorafenib had significantly higher cfDNA levels than the others (0.82 ng/μL vs 0.63 ng/μL; P = 0.006).…”