Proteomic analysis of hepatocellular carcinoma etiology and risk stratification in two prospective studies

High-throughput proteomics enable deeper insights into hepatocellular carcinoma (HCC) etiology and risk stratification. In a nested study within Prostate, Lung, Colorectal and Ovarian Screening trial (118 HCC cases, 118 controls; median follow-up=9.7 years), we examined 4,003 circulating proteins using conditional logistic regression and developed an eight-protein risk score via LASSO regression. Findings were validated in UK Biobank (50,182 participants; 36 HCC cases; median follow-up=13.9 years) using Cox regression and the C-index. In PLCO, 106 proteins were significantly associated with HCC risk; 97% of those available were replicated in UK Biobank, implicating inflammation and growth-factor signaling. The risk score demonstrated strong discrimination (C-index=0.92, 95% confidence intervals [CI] 0.84-0.97) overall and ability to stratify 8-year cumulative HCC risk in at-risk subgroups including cirrhosis (18% for higher risk vs 2% lower risk) or current/past hepatitis B/C infection (13% vs 1%). These findings support proteomic profiling for identifying the highest-risk individuals for precision surveillance.