Here, we propose to validate tissue and blood-based combinatorial biomarker panels, derived from functional pathway-specific studies, to improve the early detection of liver cancer [hepatocellular carcinoma (HCC)] and stratify populations according to their risk for developing HCC. In its early stages, HCC is curable; once advanced, HCC is associated with high mortality. Most early HCCs are undetected, demonstrating the challenge in predicting and diagnosing early HCC. Through preclinical studies that integrate analysis of human genomic data from The Cancer Genome Atlas (TCGA), mouse models, and human tissue/cell line studies, we determined that specific high-risk populations may be identified through alterations in the following biomarkers: EpCAM, Osteopontin (OPN), the polo-like kinase 1 (PLK1) the TGF-β and DNA repair members. We have established a multi-center consortium of 4 Translational Research Centers (TRCs): Johns Hopkins University (TRC1), George Washington University (TRC2), University of Texas MD Anderson Cancer Center (TRC3), University of Hawaii (TRC4). These 4 TRCs will work in collaboration with NCI to implement a multi-institutional framework to collect the highest quality biospecimens from patients with various well-defined liver pathologies and conduct specific biomarker validation studies for early detection of HCC and risk stratification of patients with cirrhosis. The central hypothesis, based upon our functional preclinical models and pilot studies in human liver disease samples, is that alterations in the above markers lead to HCC, and that aberrant expression of these can lead to early detection of HCC, as well as risk stratification. Specifically, the following biomarker panels will be assessed (a) Tissue EpCAM, OPN, PLK1 levels (Panel 1, Project 1, TRC1), (b) Tissue levels of TBR2, SPTBN1, FancD2 and Sirt6 (Panel 2, Project 2 TRC2). (c) Serum markers (Panel 3, EpCAM, OPN, TGF-β) will be tested in TRC1 and 2; (d) In circulating tumor cells (CTCs), mutational analyses (Panel 4, Smad4 and SPTBN1, Project 2, TRC2) and surface vimentin (CSV) (Panel 5, Project 3, TRC3) will be performed. Validation of candidate biomarkers (Project 4, TRC4) will also be done at TRC4, and also with collaborations in NCI, China and external cohorts, that include EDRN samples. The 4 projects will collectively address: Aim 1: EDRN Phase 2 studies (to find markers of current HCCs) in tissue only using panels 1 and 2. All samples are retrospective, collected in patients (cases) and controls. Aim 2: EDRN Phase 2 studies in blood only on panels 3, 4 and 5. Here, all samples are retrospective, collected in current cases and current controls. Aim 3: EDRN Phase 3 studies (Panel 3 markers that predict future development of HCC) in blood using longitudinal data (both retrospective and prospective). Data are collected before participants develop HCC, and they are followed over time to see who develops HCC, and multiple time points of marker data are collected and stored over time prior to tumor onset. In addition, we will maintain and share a biorepository, and collaborate with other Centers in the Translational Research Network for Liver Cancer.