Clonal heterogeneity and tumor evolution in liver cancer: the cutting edge and the future

Human hepatocellular carcinoma (HCC) is a highly heterogeneous disease consisting of cells that differ in clinically important phenotypic features. This phenotypic heterogeneity, including intertumor heterogeneity and intratumor heterogeneity, is a result of the interplay between (epi) genetic and non-genetic microenvironmental factors that shape cellular phenotypes. Intratumor heterogeneity mandates understanding of longitudinal and spatial subclonal dynamics, and adds new levels of complexity in the molecular understanding of HCC, leading to primary and secondary resistance to targeted therapies. We believe that the recognition of the importance of intratumor heterogeneity combined with the rapid development of technologies allowing its interrogation will offer insight into therapy response, tumor evolutionary histories and clinical trial design in HCC. Key words: Hepatocellular carcinoma; Tumor heterogeneity; Treatment resistance