A liquid biopsy assay for identifying early-stage hepatocellular carcinoma in asymptomatic HBsAg-seropositive individuals

With increasing knowledge on molecular tumour information, precision oncology has revolutionised the medical field over the past years. Liquid biopsy entails the analysis of circulating tumour components, such as circulating tumour DNA, tumour cells or tumour-derived extracellular vesicles, and has thus come as a handy tool for personalised medicine in many cancer entities. Clinical applications under investigation include early cancer detection, prediction of treatment response and molecular monitoring of the disease, for example, to comprehend resistance patterns and clonal tumour evolution. In fact, several tests for blood-based mutation profiling are already commercially available and have entered the clinical field.In the context of hepatocellular carcinoma, where access to tissue specimens remains mostly limited to patients with early stage tumours, liquid biopsy approaches might be particularly helpful. A variety of translational liquid biopsy studies have been carried out to address clinical needs, such as early hepatocellular carcinoma detection and prediction of treatment response. To this regard, methylation profiling of circulating tumour DNA has evolved as a promising surveillance tool for early hepatocellular carcinoma detection in populations at risk, which might soon transform the way surveillance programmes are implemented. This review summarises recent developments in the liquid biopsy oncological space and, in more detail, the potential implications in the clinical management of hepatocellular carcinoma. It further outlines technical peculiarities across liquid biopsy technologies, which might be helpful for interpretation by non-experts.

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Liquid Biopsy of Hepatocellular Carcinoma: Circulating Tumor-Derived Biomarkers

Disease Markers ◽

10.1155/2016/1427849 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 18

Author(s):

Chang-Qing Yin ◽

Chun-Hui Yuan ◽

Zhen Qu ◽

Qing Guan ◽

Hao Chen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Progression ◽

Liquid Biopsy ◽

Clinical Decision Making ◽

Early Stage ◽

Prognostic Significance ◽

Liquid Biopsies ◽

Tumor Biopsy ◽

Diagnostic Strategies ◽

Systemic Treatments

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide due to latent liver disease, late diagnosis, and nonresponse to systemic treatments. Till now, surgical and/or biopsy specimens are still generally used as a gold standard by the clinicians for clinical decision-making. However, apart from their invasive characteristics, tumor biopsy only mirrors a single spot of the tumor, failing to reflect current cancer dynamics and progression. Therefore, it is imperative to develop new diagnostic strategies with significant effectiveness and reliability to monitor high-risk populations and detect HCC at an early stage. In the past decade, the potent utilities of “liquid biopsy” have attracted intense concern and were developed to evaluate cancer progression in several clinical trials. “Liquid biopsies” represent a series of noninvasive tests that detect cancer byproducts easily accessible in peripheral blood, mainly including circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs) that are shed into the blood from the tumor sites. In this review, we focus on the recent developments in the field of “liquid biopsy” as well as the diagnostic and prognostic significance of CTCs and cfNAs in HCC patients.

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Platelets’ RNA as biomarker trove for differentiation of early-stage hepatocellular carcinoma from underlying cirrhotic nodules

PLoS ONE ◽

10.1371/journal.pone.0256739 ◽

2021 ◽

Vol 16 (9) ◽

pp. e0256739

Author(s):

Walifa Waqar ◽

Sidra Asghar ◽

Sobia Manzoor

Keyword(s):

Hepatocellular Carcinoma ◽

Late Stage ◽

Liquid Biopsy ◽

Early Stage ◽

Quantitative Real Time Pcr ◽

Roc Curve Analysis ◽

Mrna Content ◽

Early Hcc ◽

Rising Incidence ◽

Specific Mrna

Background & aims Among the multiplicity of factors involved in rising incidence of hepatocellular carcinoma (HCC)-the second deadliest cancer, late diagnosis of early-stage HCC nodules originating from late-stage cirrhotic nodules is the most crucial. In recent years, Tumor-educated platelets (TEPs) have emerged as a strong multimodal tool to be used in liquid-biopsy of cancers because of changes in their mRNA content. This study assessed the reliability of selected mRNA repertoire of platelets as biomarkers to differentiate early HCC from late-stage cirrhotic nodules. Methods Quantitative real time PCR (qRT-PCR) was used to evaluate expression levels of selected platelets-specific mRNA between HCC patients compared to cirrhosis patients. ROC curve analysis assessed the sensitivity and specificity of the biomarkers. Results RhoA, CTNNB1 and SPINK1 showed a significant 3.3-, 3.2- and 3.18-folds upregulation, respectively, in HCC patients compared to cirrhosis patients while IFITM3 and SERPIND1 presented a 2.24-fold change. Strikingly, CD41+ platelets also demonstrated a marked difference of expression in HCC and cirrhosis groups. Conclusions Our study reports liquid biopsy-based platelets mRNA signature for early diagnosis of HCC from underlying cirrhotic nodules. Moreover, differential expression of CD41+ platelets in two groups provides new insights into a probable link between CD41 expression on platelets with the progression of cirrhosis to HCC.

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Detection of early-stage hepatocellular carcinoma in asymptomatic HBsAg-seropositive individuals by liquid biopsy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1819799116 ◽

2019 ◽

Vol 116 (13) ◽

pp. 6308-6312 ◽

Cited By ~ 25

Author(s):

Chunfeng Qu ◽

Yuting Wang ◽

Pei Wang ◽

Kun Chen ◽

Minjie Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liquid Biopsy ◽

Early Stage ◽

Elevated Serum ◽

Normal Liver ◽

Protein Markers ◽

Liquid Biopsies ◽

B Virus ◽

Asymptomatic Individuals

Liquid biopsies, based on cell free DNA (cfDNA) and proteins, have shown the potential to detect early stage cancers of diverse tissue types. However, most of these studies were retrospective, using individuals previously diagnosed with cancer as cases and healthy individuals as controls. Here, we developed a liquid biopsy assay, named the hepatocellular carcinoma screen (HCCscreen), to identify HCC from the surface antigen of hepatitis B virus (HBsAg) positive asymptomatic individuals in the community population. The training cohort consisted of individuals who had liver nodules and/or elevated serum α-fetoprotein (AFP) levels, and the assay robustly separated those with HCC from those who were non-HCC with a sensitivity of 85% and a specificity of 93%. We further applied this assay to 331 individuals with normal liver ultrasonography and serum AFP levels. A total of 24 positive cases were identified, and a clinical follow-up for 6–8 mo confirmed four had developed HCC. No HCC cases were diagnosed from the 307 test-negative individuals in the follow-up during the same timescale. Thus, the assay showed 100% sensitivity, 94% specificity, and 17% positive predictive value in the validation cohort. Notably, each of the four HCC cases was at the early stage (<3 cm) when diagnosed. Our study provides evidence that the use of combined detection of cfDNA alterations and protein markers is a feasible approach to identify early stage HCC from asymptomatic community populations with unknown HCC status.

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Clinical Application Value of Circulating Cell-free DNA in Hepatocellular Carcinoma

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.736330 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yuyuan Zhang ◽

Zaoqu Liu ◽

Kun Ji ◽

Xin Li ◽

Caihong Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liquid Biopsy ◽

Clinical Decision Making ◽

Early Stage ◽

Predictive Biomarker ◽

Intrahepatic Metastasis ◽

Genetic Profile ◽

Cell Free Dna ◽

Free Dna ◽

Systemic Treatments

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and a leading cause of cancer-related deaths. Due to late diagnosis, early intrahepatic metastasis and nonresponse to systemic treatments, surgical resection and/or biopsy specimens remain the gold standard for disease staging, grading and clinical decision-making. Since only a small amount of tissue was obtained in a needle biopsy, the conventional tissue biopsy is unable to represent tumor heterogeneity in HCC. For this reason, it is imperative to find a new non-invasive and easily available diagnostic tool to detect HCC at an early stage and to monitor HCC recurrence. The past decade has witnessed considerable evolution in the development of liquid biopsy technologies with the emergence of next-generation sequencing. As a liquid biopsy approach, molecular analysis of cell-free DNA (cfDNA), characterized by noninvasiveness and real-time analysis, may accurately represent the tumor burden and comprehensively reflect genetic profile of HCC. Therefore, cfDNA may be used clinically as a predictive biomarker in early diagnosis, outcome assessment, and even molecular typing. In this review, we provide an update on the recent advances made in clinical applications of cfDNA in HCC.

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Wisp1 as an early stage marker of human hepatocellular carcinoma (HCC)?

Zeitschrift für Gastroenterologie ◽

10.1055/s-0035-1568093 ◽

2015 ◽

Vol 53 (12) ◽

Author(s):

A Dropmann ◽

T Feng ◽

T Dediulia ◽

I Ilkavets ◽

B Hofmann ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Early Stage ◽

Human Hepatocellular Carcinoma

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UTERINE LAVAGE: AN OFFICE PROCEDURE WITH A PROMISING POTENTIAL FOR DIAGNOSING EARLY-STAGE OVARIAN CANCER THROUOGH LIQUID BIOPSY

10.26226/morressier.599bdc7ad462b80296ca189a ◽

2017 ◽

Author(s):

Tamar Perri

Keyword(s):

Ovarian Cancer ◽

Liquid Biopsy ◽

Early Stage ◽

Office Procedure ◽

Uterine Lavage ◽

Early Stage Ovarian Cancer

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miR-224 is an early-stage biomarker of hepatocellular carcinoma with miR-224 and miR-125b as prognostic biomarkers

Biomarkers in Medicine ◽

10.2217/bmm-2020-0099 ◽

2020 ◽

Vol 14 (15) ◽

pp. 1485-1500

Author(s):

Lichao Yang ◽

Chunmeng Wei ◽

Yasi Li ◽

Xiao He ◽

Min He

Keyword(s):

Hepatocellular Carcinoma ◽

Systematic Review ◽

Survival Analysis ◽

Sensitivity And Specificity ◽

Poor Prognosis ◽

Early Stage ◽

Meta Analysis ◽

Benign Lesion ◽

Diagnostic Efficiency ◽

Low Expression

Aim: The aim was to systematically investigate the miRNA biomarkers for early diagnosis of hepatocellular carcinoma (HCC). Materials & methods: A systematic review and meta-analysis of miRNA expression in HCC were performed. Results: A total of 4903 cases from 30 original studies were comprehensively analyzed. The sensitivity and specificity of miR-224 in discriminating early-stage HCC patients from benign lesion patients were 0.868 and 0.792, which were superior to α-fetoprotein. Combined miR-224 with α-fetoprotein, the sensitivity and specificity were increased to 0.882 and 0.808. Prognostic survival analysis showed low expression of miR-125b and high expression of miR-224 were associated with poor prognosis. Conclusion: miR-224 had a prominent diagnostic efficiency in early-stage HCC, with miR-224 and miR-125b being valuable in the prognostic diagnosis.

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The Treatment Effect of Liver Transplantation versus Liver Resection for HCC: A Review and Future Perspectives

Cancers ◽

10.3390/cancers13153730 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3730

Author(s):

Berend R. Beumer ◽

Roeland F. de Wilde ◽

Herold J. Metselaar ◽

Robert A. de Man ◽

Wojciech G. Polak ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Liver Resection ◽

Early Stage ◽

Disease Free Survival ◽

Milan Criteria ◽

Term Survival ◽

Equal Distribution ◽

Intention To Treat ◽

Treat Analysis

For patients presenting with hepatocellular carcinoma within the Milan criteria, either liver resection or liver transplantation can be performed. However, to what extent either of these treatment options is superior in terms of long-term survival is unknown. Obviously, the comparison of these treatments is complicated by several selection processes. In this article, we comprehensively review the current literature with a focus on factors accounting for selection bias. Thus far, studies that did not perform an intention-to-treat analysis conclude that liver transplantation is superior to liver resection for early-stage hepatocellular carcinoma. In contrast, studies performing an intention-to-treat analysis state that survival is comparable between both modalities. Furthermore, all studies demonstrate that disease-free survival is longer after liver transplantation compared to liver resection. With respect to the latter, implications of recurrences for survival are rarely discussed. Heterogeneous treatment effects and logical inconsistencies indicate that studies with a higher level of evidence are needed to determine if liver transplantation offers a survival benefit over liver resection. However, randomised controlled trials, as the golden standard, are believed to be infeasible. Therefore, we suggest an alternative research design from the causal inference literature. The rationale for a regression discontinuity design that exploits the natural experiment created by the widely adopted Milan criteria will be discussed. In this type of study, the analysis is focused on liver transplantation patients just within the Milan criteria and liver resection patients just outside, hereby ensuring equal distribution of confounders.

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The APAC Score: A Novel and Highly Performant Serological Tool for Early Diagnosis of Hepatocellular Carcinoma in Patients with Liver Cirrhosis

Journal of Clinical Medicine ◽

10.3390/jcm10153392 ◽

2021 ◽

Vol 10 (15) ◽

pp. 3392

Author(s):

Joeri Lambrecht ◽

Mustafa Porsch-Özçürümez ◽

Jan Best ◽

Fabian Jost-Brinkmann ◽

Christoph Roderburg ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

At Risk ◽

Liver Cirrhosis ◽

Early Stage ◽

Treatment Options ◽

Growth Factor Receptor ◽

Serum Samples ◽

Disease Etiology ◽

Risk Patients ◽

Scoring Tool

(1) Background: Surveillance of at-risk patients for hepatocellular carcinoma (HCC) is highly necessary, as curative treatment options are only feasible in early disease stages. However, to date, screening of patients with liver cirrhosis for HCC mostly relies on suboptimal ultrasound-mediated evaluation and α-fetoprotein (AFP) measurement. Therefore, we sought to develop a novel and blood-based scoring tool for the identification of early-stage HCC. (2) Methods: Serum samples from 267 patients with liver cirrhosis, including 122 patients with HCC and 145 without, were collected. Expression levels of soluble platelet-derived growth factor receptor beta (sPDGFRβ) and routine clinical parameters were evaluated, and then utilized in logistic regression analysis. (3) Results: We developed a novel serological scoring tool, the APAC score, consisting of the parameters age, sPDGFRβ, AFP, and creatinine, which identified patients with HCC in a cirrhotic population with an AUC of 0.9503, which was significantly better than the GALAD score (AUC: 0.9000, p = 0.0031). Moreover, the diagnostic accuracy of the APAC score was independent of disease etiology, including alcohol (AUC: 0.9317), viral infection (AUC: 0.9561), and NAFLD (AUC: 0.9545). For the detection of patients with (very) early (BCLC 0/A) HCC stage or within Milan criteria, the APAC score achieved an AUC of 0.9317 (sensitivity: 85.2%, specificity: 89.2%) and 0.9488 (sensitivity: 91.1%, specificity 85.3%), respectively. (4) Conclusions: The APAC score is a novel and highly accurate serological tool for the identification of HCC, especially for early stages. It is superior to the currently proposed blood-based algorithms, and has the potential to improve surveillance of the at-risk population.

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