Hepatocellular carcinoma: novel molecular approaches for diagnosis, prognosis, and therapy

Abstract

The genomic era is changing the understanding of cancer, although translation of the vast amount of data available into decision-making algorithms is far from reality. Molecular profiling of hepatocellular carcinoma (HCC), the most common cause of death among cirrhotic patients and a fast-growing malignancy in Western countries, is enabling the advancement of novel approaches to disease diagnosis and management. Most HCCs arise on a cirrhotic liver, and predictably, an accurate genomic characterization will allow the identification of procarcinogenic signals amenable to selective targeting by chemopreventive strategies. Molecular diagnosis is currently feasible for small tumors, but it has not yet been formalized by scientific guidelines. Molecular treatment is a reality: Sorafenib confers unprecedented survival benefits in patients at advanced stages. Genomic information from tumor and nontumoral tissue will aid prognosis prediction and facilitate the identification of oncogene addiction loops, providing the opportunity for more personalized medicine.

Figure 1

Prognosis prediction in HCC will likely depend on 2 factors: 1. Clinical staging systems capturing tumor status, liver functional status and health condition). 2. Genomic data capturing gene profiles from tumor and non-tumoral cirrhotic tissue. Clinical systems (e.g. BCLC) offer a reliable framework to accurately predict prognosis in most patients. In addition, genomic profiling of the tumor and the surrounding tissue will complement clinical data to decrease misclassification rates. However, the relative importance of each component will depend on the stage of the disease. The top panel summarizes the different stages, therapy, and predicted survival in HCC according to BCLC staging system. The lower panels show the relative weight for survival prediction of genomic data from adjacent and tumoral tissue. Basically, in patients with very early HCC treated with surgical resection, survival is determined by risk of developing a de novo HCC, and this is genetically encoded in the surrounding tissue. As cancer progresses, genomic data from de tumor becomes more informative in terms of survival prediction. This is due to the fact that several pathological features related to patient survival (e.g. vascular invasion, satellites, poor differentiation) are encoded in the tumor. In these stages, patient survival will no longer depend so stringently on the risk for developing a de novo HCC, since the risk of death is more related to local disease and distant progression. Interestingly, local progression of the disease (i.e. intrahepatic metastasis) in advanced stages is genetically encoded in the adjacent tissue.