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

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.

Cell-free nucleic acid patterns in disease prediction and monitoring—hype or hope?

“…ctDNA was described to be the tumour-derived fraction of cell-free DNA secreted into the blood [ 119 ]. ctDNA patterns in blood are considered as being a potent analytical option alternative to solid tumour biopsies for cancer detection and monitoring, due to rapid, non-invasive and cost-effective biomarker identification [ 120 ]. Besides cfDNA/ctDNA, malignancy-related blood patterns include circulating miRNA, circulating tumour cells (CTCs) and exosomes [ 121 , 122 ].…”

Liquid Biopsy is Instrumental for 3PM Dimensional Solutions in Cancer Management

“…Circulating tumor cell-free DNA (ctDNA) is defined as tumor-derived extracellular nucleic acid in cell-free plasma or serum that is currently gaining a promising potential as a novel diagnostic and prognostic tool in cancer management [ 86 , 93 , 101 ]. Peripheral blood is the most common source of ctDNA but it could be detected also in other biofluids such as saliva, urine, ascites, and PE [ 102 ]. Optimal pre-analytical and analytical procedures are required for appropriate sample collection, centrifugation, storage, and DNA isolation from biological sources due to the contamination, low concentration, and high fragmentation of genomic DNA [ 42 ].…”

“…Optimal pre-analytical and analytical procedures are required for appropriate sample collection, centrifugation, storage, and DNA isolation from biological sources due to the contamination, low concentration, and high fragmentation of genomic DNA [ 42 ]. Despite the fact that a higher concentration of cell-free DNA is generally associated with serum, it is not a preferable liquid biopsy sample because of the contamination during the storage procedure [ 42 , 102 ] due to potentially high content of DNA released from lysis of circulating blood cells [ 103 ]. However, the comparison of the detection of the BRAF V600E-targetable mutation by dPCR from ctDNA and EV-derived DNA in plasma, serum, and CSF revealed serum to be more promising than plasma in liquid biopsy from pediatric central nervous tumors [ 39 ].…”

Hepatocellular Carcinoma: A Review

“…The Barcelona clinic liver cancer (BCLC) staging system (25) is most accepted in various guidelines and practiced (Figure 3). The staging in BCLC is linked to most appropriate therapy for HCC according to the stage of tumor which includes nodule size and number along <2 cm in size, predicting the prognosis of the lesion based upon certain genetic mutations and better selection of therapeutic modality based upon immunogenetics (21,22).…”