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Review
. 2020 Mar 5;16(9):1551-1562.
doi: 10.7150/ijbs.44024. eCollection 2020.

Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma

Xiaolin Wu  1 , Jiahui Li  1 , Asmae Gassa  2 , Denise Buchner  1 , Hakan Alakus  1 , Qiongzhu Dong  3 , Ning Ren  4 , Ming Liu  5 , Margarete Odenthal  6 , Dirk Stippel  1 , Christiane Bruns  1 , Yue Zhao  1   7 , Roger Wahba  1
Affiliations
Review

Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma

Xiaolin Wu et al. Int J Biol Sci. .

Abstract

As one of the most common malignant tumors worldwide, hepatocellular carcinoma (HCC) is known for its poor prognosis due to diagnosis only in advanced stages. Nearly 50% of the patients with the first diagnosis of HCC die within a year. Currently, the advancements in the integration of omics information have begun to transform the clinical management of cancer patients. Molecular profiling for HCC patients is in general obtained from resected tumor materials or biopsies. However, the resected tumor tissue is limited and can only be obtained through surgery, so that dynamic monitoring of patients cannot be performed. Compared to invasive procedures, circulating tumor DNA (ctDNA) has been proposed as an alternative source to perform molecular profiling of tumor DNA in cancer patients. The detection of abnormal forms of circulating cell-free DNA (cfDNA) that originate from cancer cells (ctDNA) provides a novel tool for cancer detection and disease monitoring. This may also be an opportunity to optimize the early diagnosis of HCC. In this review, we summarized the updated methods, materials, storage of sampling, detection techniques for ctDNA and the comparison of the applications among different biomarkers in HCC patients. In particular, we analyzed ctDNA studies dealing with copy number variations, gene integrity, mutations (RAS, TERT, CTNNB1, TP53 and so on), DNA methylation alterations (DBX2, THY1, TGR5 and so on) for the potential utility of ctDNA in the diagnosis and management of HCC. The biological functions and correlated signaling pathways of ctDNA associated genes (including MAPK/RAS pathway, p53 signaling pathway and Wnt-β catenin pathway) are also discussed and highlighted. Thus, exploration of ctDNA/cfDNA as potential biomarkers may provide a great opportunity in future liquid biopsy applications for HCC.

Keywords: biomarker, hepatocellular carcinoma, liver cancer; cell-free DNA; circulating tumor DNA; liquid biopsy.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Main mutation pathways and functions in HCC development. MAPK/RAS pathway(marked with yellow), TERT mutation(marked with blue), p53 signaling pathway(marked with green), Wnt-β catenin pathway(marked with gray), and SWI/SNF complex related pathway(marked with light red) are the common centralized signaling pathways. They affect tumorigenesis and progression of hepatocellular carcinoma, involving several common oncogenes and tumor suppressors. Corresponding functions include proliferation, immortalization, genomic stability, cell differentiation and survival. The mutation genes detected in ctDNA show significant roles in pathways (Red box).
Figure 2
Figure 2
Functions of the genes with methylation. The functions of the genes with methylation (marked with red) mainly focus on several aspects: DNA damaged, metabolic regulation, apoptosis, G protein-coupled signal transmission, cell division, and some plasma protein release. RUNX2 has an influence on DNA damage(marked with blue); THY1, ST8SIA6, MT1M, MT1G, and RGS10 participate in the metabolism process (marked with green); VIM has a connection with apoptosis (marked with yellow); TGR5(GPBAR1) is a G-protein-coupled bile acid receptor for bile acid mediating; SEPT9 plays a critical role of cytokinesis and INK4A (CDKN2A) is a cell cycle inhibitor(marked with light red); FBLIN1 is related to plasma glycoprotein generation(marked with orange).
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