Identification of mutations in circulating cell-free tumour DNA as a biomarker in hepatocellular carcinoma

Howell, Jessica; Atkinson, Stephen R.; Pinato, David J.; Knapp, S.; Ward, Caroline; Minisini, Rosalba; Burlone, Michela Emma; Leutner, Monica; Pirisi, Mario; Büttner, Reinhard; Khan, Shahid A.; Thursz, Mark; Odenthal, Margarete; Sharma, Rohini

doi:10.1016/j.ejca.2019.04.014

Cited by 60 publications

(63 citation statements)

References 24 publications

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“…In this regard, ultra-deep targeted sequencing for all exons of the 58 most frequently mutated genes in HCC reported an overall detection rate for tissue mutations in plasma cfDNA of 43% (9/21) [102]. A more recent study showed that all the mutations detected in plasma cfDNA matched HCC tissue DNA but not the opposite, pointing towards a high specificity but low sensitivity of plasma cfDNA as an HCC biomarker [103].…”

Section: Cfdnamentioning

confidence: 99%

Liquid Biopsies in Hepatocellular Carcinoma: Are We Winning?

Mocan

Simão

Castro

et al. 2020

JCM

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Hepatocellular carcinoma (HCC) represents the sixth most common cancer worldwide and the third most common cause of cancer-related death. One of the major problems faced by researchers and clinicians in this area is the lack of reliable disease biomarkers, which would allow for an earlier diagnosis, follow-up or prediction of treatment response, among others. In this regard, the “HCC circulome”, defined as the pool of circulating molecules in the bloodstream derived from the primary tumor, represents an appealing target, the so called liquid biopsy. Such molecules encompass circulating tumor proteins, circulating tumor cells (CTCs), extracellular vesicles (EVs), tumor-educated platelets (TEPs), and circulating tumor nucleic acids, namely circulating tumor DNA (ctDNA) and circulating tumor RNA (ctRNA). In this article, we summarize recent findings highlighting the promising role of liquid biopsies as novel potential biomarkers in HCC, emphasizing on its clinical performance.

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Section: Cfdnamentioning

confidence: 99%

Liquid Biopsies in Hepatocellular Carcinoma: Are We Winning?

Mocan

Simão

Castro

et al. 2020

JCM

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“…Simultaneously, the frequency of common gene mutations in HCC may vary in different cohorts. For example, ARID1A was detected as the gene with the highest mutation rate in ctDNA of HCC patients in some European cohorts [36] instead of TP53.…”

Section: Gene Mutationmentioning

confidence: 99%

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

Gassa

et al. 2020

Int. J. Biol. Sci.

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111

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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.

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“…Recently, studies have reported the detection of plasma ctDNA alterations by sequencing and protein markers in serum to identify early-stage HCC [33][34][35][36] , but their comparisons were made predominantly against healthy controls or reduced sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Urine biomarker: novel approach to hepatocellular carcinoma screening

Kim

Hamilton

Lin

et al. 2020

Preprint

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Background & AimsContinued limitations in hepatocellular carcinoma (HCC) screening have led to late diagnosis with poor survival, despite well-defined high-risk patient populations. Our aim is to develop a non-invasive urine circulating tumor DNA (ctDNA) biomarker panel for HCC screening to aid in early detection.MethodsCandidate ctDNA biomarkers was prescreened in urine samples obtained from HCC, cirrhosis, and hepatitis patients. Then, 609 patient urine samples with HCC, cirrhosis, or chronic hepatitis B were collected from five academic medical centers and evaluated by serum alpha feto-protein (AFP) and urine ctDNA panel using logistic regression, a Two-Step machine learning algorithm, and iterated 10-fold cross-validation.ResultsMutated TP53, and methylated RASSF1a and GSTP1, were selected for the urine ctDNA panel. The sensitivity of AFP-alone (9.8 ng/mL cut-off) to detect HCC was 71% by Two-Step. The combination of ctDNA and AFP increased the sensitivity to 81% at a specificity of 90%. The AUROC for the combination of ctDNA and AFP vs. AFP-alone were 0.925 (95% CI, 0.924-0.925) and 0.877 (95% CI, 0.876-0.877), respectively. Notably, among the patients with AFP <20 ng/mL, the combination panel correctly identified 64% of HCC cases. The panel performed superiorly to AFP-alone in early-stage HCC (BCLC A) with 80% sensitivity and 90% specificity. In an iterated 10-fold cross-validation analysis, the AUROC for the combination panel was 0.898 (95% CI, 0.895-0.901).ConclusionsThe combination of urine ctDNA and serum AFP can increase HCC detection rates including in those patients with low-AFP. Given the ease of collection, a urine ctDNA panel could be a potential non-invasive HCC screening test.

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Identification of mutations in circulating cell-free tumour DNA as a biomarker in hepatocellular carcinoma

Cited by 60 publications

References 24 publications

Liquid Biopsies in Hepatocellular Carcinoma: Are We Winning?

Liquid Biopsies in Hepatocellular Carcinoma: Are We Winning?

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

Urine biomarker: novel approach to hepatocellular carcinoma screening

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