The application of molecular profiling and proteomics in the study of liver cancers

Abstract

Background: Hepatocellular cancer [1] is increasing worldwide. The majority are detected too late for curative surgery as effective identification of the at risk population and their subsequent surveillance is inadequate. My specific aims were to study and characterise our own patients, evaluating the known and predicted biomarkers for HCC in patients with non-alcoholic fatty liver disease and exploring novel biomarker methodologies for the detection of either cirrhosis or HCC complicating it. Methods: Details of all HCC patients presenting to the Newcastle hepatopancreatobiliary (HPB) multidisciplinary team were recorded in an NHS intranet database, and a subset were consented for tissue collection. Established and candidate biomarkers were assessed in serum by western blotting and/or ELISA assay and the role of microarray analysis of HepG2 cells, and 2D-gel electrophoresis of immunodepleted serum in novel candidate biomarker identification were explored. Results: The number of HCC cases referred has increased dramatically over the last decade, as has the numbers arising in a background of non-alcoholic fatty liver disease (NAFLD). In our cohort, patients with earlier stage cancers detected by either - surveillance or incidentally had a better prognosis, but only 10% were eligible for definitive treatment. While HCC patients treated with liver transplant had an overall 5 year survival was 62.1%, the median survival of the transplant cohort was 137 months. Exploration of serum levels of Glypican 3, Squamous Cell Carcinoma Antigen-1 and follistatin were poor surveillance biomarkers, but the combination of Alpha-fetoprotein and Protrhombin induced by vitamin-K absence was encouraging. Serum proteomic analysis in a small subgroup identified four isoforms of apolipoproteins as well as CD5L as differentially expressed between patients with no cirrhosis, cirrhosis and HCC, although subsequent CD5L ELISA failed to confirm its ability to specifically detect HCC. Discussion: While the incidence of HCC is increasing, the prognosis for those affected remains poor. Biomarkers identifying both the at risk individuals and those with cancer are urgently required.