Intratumor Heterogeneity in Hepatocellular Carcinoma: Challenges and Opportunities

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.

Keywords: TERT; cancer; intratumor heterogeneity; liver cancer; single-cell sequencing; therapy resistance; β-catenin.

Figure 1

Theories of tumor evolution. (A) Clonal evolution, where all tumor cells diverge from a common ancestor with a fitness advantage, and subclones emerge with acquired genomic alterations. (B) Neutral evolution, where mutations randomly accumulate over time with no one population having a selective advantage. (C) Punctuated evolution, where a large number of genetic alterations occur at a point in time, but only a few dominant clones persist. (D) Collision tumor, where physically distant clonal cell populations converge as they proliferate, eventually colliding and forming a single tumor.

Figure 2

Role of ITH in targeted therapy resistance and treatment stratagem. (A) Monotherapies target a subset of tumor cells, resulting in incomplete tumor attrition. (B) Combination therapies target multiple oncogenic pathways, potentially resulting in tumor regression. However, recurrent tumors can occur when pre-existing ITH or ITH induced by cell–cell/cell–microenvironment interactions results in the emergence of genetically and/or epigenetically resistant clones. (C) Combination therapy administered with alternating periods without treatment allows for the disappearance and re-emergence of drug-sensitive clones. Competition between clones limits the emergence of resistant clones.