Molecular classification and novel targets in hepatocellular carcinoma: recent advancements

Abstract

Hepatocellular carcinoma (HCC) is one of most lethal cancers worldwide. Strategic decisions for the advancement of molecular therapies in this neoplasm require a clear understanding of its molecular classification. Studies indicate aberrant activation of signaling pathways involved in cellular proliferation (e.g., epidermal growth factor and RAS/mitogen-activated protein kinase pathways), survival (e.g., Akt/mechanistic target of rapamycin pathway), differentiation (e.g., Wnt and Hedgehog pathways), and angiogenesis (e.g., vascular endothelial growth factor and platelet-derived growth factor), which is heterogeneously presented in each tumor. Integrative analysis of accumulated genomic datasets has revealed a global scheme of molecular classification of HCC tumors observed across diverse etiologic factors and geographic locations. Such a framework will allow systematic understanding of the frequently co-occurring molecular aberrations to design treatment strategy for each specific subclass of tumors. Accompanied by a growing number of clinical trials of molecular targeted drugs, diagnostic and prognostic biomarker development will be facilitated with special attention on study design and with new assay technologies specialized for archived fixed tissues. A new class of genomic information, microRNA dysregulation and epigenetic alterations, will provide insight for more precise understanding of disease mechanism and expand the opportunity of biomarker/therapeutic target discovery. These efforts will eventually enable personalized management of HCC.

Figure 1

Global overview of molecular classification of HCC. Correspondence between subclasses defined by a meta-analysis (upper panel) and subclasses/signatures in literatures (lower panel, see Table 1 for the details) was evaluated using Gene Set Enrichment Analysis with a significance threshold of false discovery rate <0.25.

Figure 2

(A) Hazard of HCC recurrence according to the mechanism. (B) Hazard of HCC recurrence in early stage (left panel) and advanced stage (right panel) HCC. Solid line indicates the risk of tumor sell dissemination from the primary tumors. Dashed line indicates the risk of de novo cancers arisen from the carcinogenic “field effect”.