Genetic Biomarkers For Hepatocellular Carcinoma In The Era Of Precision Medicine

Abstract

Being one of the most lethal cancers that exhibit high levels of heterogeneity, hepatocellular carcinoma (HCC) is associated with diverse oncogenic pathways underpinned by varied driver genes. HCC can be induced by different etiological factors including virus infection, toxin exposure or metabolic disorders. Consequently, patients may display varied genetic profiles, and may respond differently to the treatments involving inhibition of target pathways. These DNA/RNA mutations, copy number variations, chromatin structural changes, aberrant expression of non-coding RNAs and epigenetic modifications were considered as biomarkers in the application of precision medication. To explore how genetic testing could contribute to early diagnosis, prognosis, treatment and postoperative monitoring of HCC, we conducted a systematic review of genetic markers associated with different pathologies. Moreover, we summarized on-going clinical trials for HCC treatment, including the trials for multiple kinase inhibitors and immune checkpoint blockade (ICB). The efficacy of ICB treatment in HCC is not as good as what was observed in lung cancer and melanoma, which might be due to the heterogeneity of the microenvironment of the liver.

Keywords: clinical trials; genetic biomarkers; genomic sequencing; hepatocellular carcinoma.

Figure 1

Signaling pathways affected by the etiological factors of HCC. HBV/HCV infection, alcohol consumption, aflatoxin exposure, NAFLD and metabolic disorders may trigger HCC by manipulating diverse signaling pathways. Abbreviations: ADGRB1, adhesion G protein-coupled receptor B1 gene; AKT, protein kinase B; CPT2, carnitine o-palmitoyltransferase 2 gene; ER, endoplasmic reticulum; FAS, fas receptor; KCTD17, potassium channel tetramerization domain containing 17; NF-κB, nuclear factor-κB; NANOG, homeobox protein; PHLPP2, PH domain and leucine-rich repeat protein phosphatase; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; TLR4, Toll-like receptor 4; TNFα, tumor necrosis factor; TWIST1, twist-related protein 1; UPR, unfolded protein response.

Figure 2

Genetic biomarkers for HCC early diagnosis. Characteristics of the circulating genetic materials can be applied in HCC early diagnosis including somatic mutations, DNA methylation, exosome, micro RNA (miRNA), long non-coding RNA (lncRNA), and physical characteristics of circulating tumor DNA (ctDNA).

Figure 3

Pathways and molecules inhibited by sorafenib, regorafenib, cabozantinib, ramucirumab and lenvatinib. Red Xs indicate inhibition by sorafenib, blue Xs indicate inhibition by regorafenib, yellow Xs indicate inhibition by cabozantinib, green Xs indicate inhibition by lenvatinib, and purple Xs indicate inhibition by ramucirumab. Abbreviations: ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; Raf, RAF proto-oncogene serine/threonine-protein kinase; Ras, Ras GTPases; FGFR, fibroblast growth factor receptor; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor; RTKs, receptor tyrosine kinase; PDGFRA, platelet-derived growth factor receptor A; EGFR, epidermal growth factor receptor; PI3K, phosphoinositide 3-kinase; Mcl-1, induced myeloid leukemia cell differentiation protein; eIF4E, eukaryotic translation initiation factor 4E.

Figure 4

Pathways and molecules targeted by immunotherapy. Immune checkpoint blockade drugs suppress cancer development by inhibiting PD-1 (nivolumab, pembrolizumab), PD-L1 (durvalumab, atezolzumab) and CTLA-4 (Tremelimumab). Abbreviations: CTLA-4, cytotoxic lymphocyte associated protein 4; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; MHC, major histocompatibility complex; TCR, T-cell receptor.

Figure 5

Geographic distribution of trails in relation to HCC incidence rates. The Age-standardized HCC incidence per 100,000 people of each country or region was reflected by a color intensity map, white corresponds to low incidence rate whereas black represent high incidence rate. The clinical trials for different drugs were labeled by circles and mapped based on their locations. The diameter of the circle correlates to the size of the trial. Data updated on 10th of September 2019.