Hepatocellular carcinoma (HCC) is one of the fastest-growing cause of cancer death in the U.S. and it is projected to be the 3rd leading cause of cancer death in the U.S. by 2040 given the poor effectiveness of current HCC risk stratification and early detection strategies. Specifically, HCC screening is recommended in all patients with cirrhosis, despite annual HCC risk varying between 1-4%/year, highlighting a need for risk stratification biomarkers. HCC screening is performed using abdominal ultrasound and the serum biomarker alpha fetoprotein (AFP); however, this strategy misses over one-third of HCCs at an early stage and results in screening harms in many patients. The goal of our Clinical Validation Center for HCC (CVC-HCC) is to validate novel blood and imaging biomarkers in phase I-III studies to improve HCC risk stratification and early detection. Translation of HCC biomarkers to practice has been hampered by a dearth of high-quality sample sets including both stored blood and imaging. Existing sample sets also primarily include patients with cirrhosis from active viral hepatitis, with limited applicability to contemporary populations who primarily have cured viral hepatitis or non-viral causes of liver disease. Our CVC will create a contemporary resource with blood and imaging data to allow for rapid validation of promising biomarkers for HCC risk-stratification and early detection in phase I-III studies. A specific population in need of better biomarkers is patients with indeterminate liver nodules (ILNs) on diagnostic CT or MRI, which are observed in over one-fourth of patients undergoing HCC screening and have a high, yet variable, risk for developing into HCC (annual risk ~6-10%/year). Our group has validated a novel bloodbased biomarker, PLSec, for risk stratification and a biomarker panel, GALAD, for early HCC detection in patients with cirrhosis and herein propose to perform a phase II-III biomarker study to evaluate them in patients with ILNs. Our team includes national leaders in HCC screening, imaging, and biomarker validation. We are leading efforts to evaluate HCC biomarkers including the EDRN-funded Hepatocellular Early Detection Strategy (HEDS) Study, NCI-funded Translational Liver Cancer (TLC) Consortium, and CPRIT-funded Texas HCC Consortium. We will leverage existing infrastructure across five health systems to create two novel resources not offered by the current sample sets including (1) a biorepository with both blood and imaging data from patients, with and without HCC, representing contemporary etiologies of liver disease for Phase II studies and (2) a prospective cohort of patients with ILNs to evaluate HCC risk stratification and early detection biomarkers in Phase III studies using a prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) design. We will work with the BCCs and DMCC to evaluate novel biomarkers, facilitating contributions to trans-network projects. Overall, our CVCHCC will lead to significant advances in phase I-III validation of novel biomarkers for HCC risk stratification and early detection, areas of need that will facilitate development of well-designed phase IV clinical utility trials.