Intratumor Heterogeneity in Hepatocellular Carcinoma: Challenges and Opportunities

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is a deadly form of liver cancer that has poor patient outcomes and survival. Unlike many other cancers, HCC has not seen the benefit of individualized treatment. Part of the reason HCC is hard to treat is due to differences among distinct regions of each tumor, also known as intratumor heterogeneity (ITH). In this review, we summarize what is known about ITH in HCC, describe how it influences tumor behavior and treatment strategies, and discuss future research directions for ITH and HCC. ABSTRACT: Hepatocellular carcinoma (HCC) represents a leading cause of cancer-related death, but it remains difficult to treat. Intratumor genetic and phenotypic heterogeneity are inherent properties of breast, skin, lung, prostate, and brain tumors, and intratumor heterogeneity (ITH) helps define prognosis and therapeutic response in these cancers. Several recent studies estimate that ITH is inherent to HCC and attribute the clinical intractability of HCC to this heterogeneity. In this review, we examine the evidence for genomic, phenotypic, and tumor microenvironment ITH in HCC, with a focus on two of the top molecular drivers of HCC: β-catenin (CTNNB1) and Telomerase reverse transcriptase (TERT). We discuss the influence of ITH on HCC diagnosis, prognosis, and therapy, while highlighting the gaps in knowledge and possible future directions.