The role of molecular enrichment on future therapies in hepatocellular carcinoma  Jean-Charles Nault, Peter R. Galle, Jens U. Marquardt  Journal of Hepatology  Volume 69, Issue 1, Pages 237-247 (July 2018) DOI: 10.1016/j.jhep.2018.02.016 Copyright © 2018 European Association for the Study of the Liver Terms and Conditions

Fig. 1 Molecular classification of hepatocellular carcinoma. The main molecular subgroups of HCC were identified by transcriptomic analysis and corresponding correlation with genetic alterations, clinical and histological features. Expression of stem cell markers such as EPCAM, CK7 and CK19 identify HCC with stem cell features that are more frequent in HCC caused by chronic HBV infection. Macrotrabecular massive HCC often display TP53 mutations as well as FGF19 amplification. The subtype is generally characterised by poor prognosis with high rates of tumour relapse and death. Steatohepatitic HCC harbour activation of the JAK/STAT pathway and represent only a small percentage of the “hepatocytic like” molecular subgroup. HCC with CTNNB1 mutations are characterised by the presence of cholestasis and by overexpression of glutamine synthase and nuclear translocation of B-catenin in the tumour. IHC,immunohistochemistry. Journal of Hepatology 2018 69, 237-247DOI: (10.1016/j.jhep.2018.02.016) Copyright © 2018 European Association for the Study of the Liver Terms and Conditions

Fig. 2 Prognostic molecular signatures of hepatocellular carcinoma. The main determinants of early and late tumour relapse, in tumorous and non-tumorous liver, after curative resection of HCC are shown. Biological, clinical and histological features of the tumour predict early recurrence due to HCC intrahepatic metastasis, whereas biology of cirrhotic liver and severity of underlying liver disease predict late relapse due to de novo carcinogenesis. Journal of Hepatology 2018 69, 237-247DOI: (10.1016/j.jhep.2018.02.016) Copyright © 2018 European Association for the Study of the Liver Terms and Conditions

Fig. 3 Putative (adaptive) design for future clinical trials in HCC. Hepatocellular cancers are molecularly and phenotypically diverse. Mandatory biopsies and collection of fresh tissue followed by application of next-generation diagnostic technologies might help to stratify patients according to their dominant molecular alterations. Grouping patients according to respective actionable molecular alterations and assigning them to a specific targeted approach might yield increased therapeutic efficacy. Given the pronounced intrahepatic heterogeneity, sequential biopsy and re-assessment of the molecular profiles might be necessary to achieve durable treatment response. Journal of Hepatology 2018 69, 237-247DOI: (10.1016/j.jhep.2018.02.016) Copyright © 2018 European Association for the Study of the Liver Terms and Conditions