Abstract
Simple SummaryHepatocellular 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.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.
Highlights
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality [1]
Using single-cell sequencing, Ho et al showed that single cells isolated from patient-derived tumor xenografts from human HCC could be divided into two subpopulations with similar mutational signatures based on epithelial cell adhesion molecule expression (EpCAM+ or EpCAM−), indicating that these two populations differed at the level of the transcriptome [34]
Presented a case of a patient with intraventricular meningioma with morphological heterogeneity and found that Telomerase reverse transcriptase (TERT) mRNA expression was low in grade I area of the meningioma but identified the same TERT promoter mutations (TPMs) (C228T) in both the grade II and III sections leading to increased TERT expression in high-grade areas [89]
Summary
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality [1]. Regardless of etiology, HCC has few druggable targets, which makes treatment of advanced. The multikinase inhibitor sorafenib extends survival by 4.3 months (95% CI, 4.0 to 5.6), and the combination of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab and the immune checkpoint inhibitor atezolizumab extends overall survival by 6.8 months (95% CI, 5.7 to 8.3) [2]. Do these first-line chemotherapies only modestly improve survival, but molecular testing for guiding HCC treatment is used little, if at all [3], underscoring the need for new drug development strategies in HCC. We discuss the influence of ITH on HCC diagnosis, prognosis, and therapy
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