ABSTRACT
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-ß 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-ß) 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.