Molecular classification of hepatocellular carcinoma: The view from metabolic zonation

Hepatocellular carcinomas (HCCs) arise from diverse etiological backgrounds and display remarkable biological and clinical heterogeneity. Unsupervised analyses of gene expression profiles variably subdivide HCCs into between two and six subclasses with distinct transcriptomic profiles and clinicopathologic features. Nevertheless, HCC molecular subclassification has not been implemented in the clinic, hampered, in part, by a lack of consensus between the various classifications and their prognostic and, in particular, predictive implications. Sorafenib, the only approved systemic treatment, on average prolongs patient survival by 2.8 months. However, robust predictive biomarkers for sorafenib response have not been defined. Indeed, prognostication and treatment decisions for HCC patients are currently made primarily based on the Barcelona Clinic Liver Cancer (BCLC) staging system. Nonetheless, several recurrent themes have emerged from the molecular analyses. HCCs can be broadly classified as proliferative and nonproliferative in roughly equal proportions. Compared to nonproliferative HCCs, proliferative HCCs are typically more aggressive and less differentiated and are frequently associated with high serum a-fetoprotein (AFP) levels, TP53 mutations, and poor outcome. Furthermore, proliferative HCCs may display transforming growth factor beta (TGF-b), MET, AKT, and/or insulin-like growth factor 2 pathway activation and/or the progenitor cell phenotype. By contrast, the nonproliferative subgroup appears to be heterogeneous with less-certain biological significance. Whereas a subset ( 30%) of the nonproliferative HCCs harbor mutations in b-catenin (encoded by catenin beta-1 [CTNNB1]) and show bcatenin pathway activation, there is no consensus on the distinguishing features of the remaining nonproliferative HCCs. In the current issue of HEPATOLOGY, D esert et al. further our understanding of nonproliferative HCCs through the lens of the metabolic zonation program of the liver. Liver parenchymal cells display a gradient of metabolic processes along the porto-central axis relative to the vascular structure of the liver (Fig. 1). For instance, gluconeogenesis and urea synthesis are primarily performed by hepatocytes near the portal vein (“periportal”), whereas lipogenesis and glycolysis are increased on the central end (“perivenous” or “pericentral”). b-catenin-mediated Wnt signaling and hepatocyte nuclear factor 4 alpha (HNF4A)-regulated gene networks play important roles in governing metabolic zonation, where in the periportal hepatocytes, T-cell factor 4 (TCF4) induces the transcription of HNF4A-regulated genes in the absence of b-catenin, and in the periportal hepatocytes, b-catenin allows TCF4 to bind to Wnt-response elements, thus inducing the transcription of b-catenin-induced genes. Through a meta-analysis of 1,113 HCCs previously profiled using gene expression microarrays, D esert et al. report that nonproliferative HCCs are divided into two Abbreviations: AFP, a-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CTNNB1, catenin beta-1; ECM, extracellular matrix; GLUL, glutamate-ammonia ligase; HAL, histidine ammonia lyase; HCCs, hepatocellular carcinomas; HNF4A, hepatocyte nuclear factor 4 alpha; LRG5, leucine-rich repeat-containing G-protein coupled receptor 5; ODAM, odontogenic ameloblast-associated protein; PP, periportal; PV, perivenous; TCF4, T-cell factor 4; TGF-b, transforming growth factor beta; TNM, tumor node metastasis; VNN1, vanin 1.