A blood-based prognostic liver secretome signature and long-term hepatocellular carcinoma risk in advanced liver fibrosis

Background: Accurate non-invasive prediction of long-term hepatocellular carcinoma (HCC) risk in advanced liver fibrosis is urgently needed for cost-effective HCC screening; however, this remains an unmet need. Methods: A serum protein-based prognostic liver secretome signature (PLSec) was bioinformatically derived from previously validated hepatic transcriptome signatures and optimized in 79 patients with advanced liver fibrosis. We independently validated PLSec for HCC risk in 331 cirrhosis patients with mixed etiologies (validation set 1 [V1]) and thereafter developed a score with clinical prognostic variables. The score was then validated in 2 independent cohorts: V2, 164 patients with advanced liver fibrosis due to hepatitis C virus (HCV) infection cured after direct-acting antiviral therapy, and V3, 146 patients with advanced liver fibrosis with successfully treated HCC and cured HCV infection. Findings: An 8-protein blood-based PLSec recapitulated transcriptome-based hepatic HCC risk status. In V1, PLSec was significantly associated with incident HCC risk (adjusted hazard ratio [aHR], 2.35; 95% confidence interval [CI], 1.30–4.23). A composite score with serum α-fetoprotein (PLSec-AFP) was defined in V1 and validated in V2 (adjusted odds ratio, 3.80 [95% CI, 1.66–8.66]) and V3 (aHR, 3.08 [95% CI, 1.78–5.31]; c-index, 0.74). PLSec-AFP outperformed AFP alone (Brier score, 0.165 versus 0.186 in V2 and 0.196 versus 0.206 in V3, respectively). Conclusions: The blood-based PLSec-AFP can accurately stratify patients with advanced liver fibrosis for long-term HCC risk and thereby guide risk-based tailored HCC screening. Funding: Uehara Memorial Foundation, US NIH (DK099558, CA233794, CA226052, CA222900, CA230694, CA230669, and CA237659), European Commission (ERC-2014-AdG-671231), Cancer Prevention and Research Institute of Texas (RR180016), LABEX HepSYS (ANR-10-LABX-0028_HEPSYS), ARC Foundation (IHU201901299), IUF, Inserm Plan Cancer (HCCMICTAR), and MGH Research Scholars Program.