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      Biomarkers in Hepatocellular Carcinoma: Diagnosis, Prognosis and Treatment Response Assessment

      review-article
      Author(s): 1 , 2 , 3 , 4 , *
      Publication date (Electronic):
      Journal: Cells
      Publisher: MDPI
      Keywords: liver cancer, biological, markers

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          Abstract

          Hepatocellular carcinoma (HCC) is one of the main cancer-related causes of death worldwide. Thus, there is a constant search for improvement in screening, diagnosis, and treatment strategies to improve the prognosis of this malignancy. The identification of useful biomarkers for surveillance and early HCC diagnosis is still deficient, with available serum biomarkers showing low sensitivity and heterogeneous specificity despite different cut-off points, even when assessed longitudinally, or with a combination of serum biomarkers. In contrast, HCC biomarkers used for prognostic (when associated with clinical outcomes) or predictive purposes (when associated with treatment response) may have an increased clinical role in the near future. Furthermore, some serum biomarkers are already implicated as a treatment selection tool, whether to provide access to certain therapies or to assess clinical benefit after treatment. In the present review we will discuss the clinical utility and foreseen future of HCC biomarkers implicated in surveillance, diagnosis, prognosis, and post-treatment assessment.

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          Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

          (2017)
          Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole exome sequencing and DNA copy number analyses, and 196 HCC also by DNA methylation, RNA, miRNA, and proteomic expression. DNA sequencing and mutation analysis identified significantly mutated genes including LZTR1 , EEF1A1 , SF3B1 , and SMARCA4 . Significant alterations by mutation or down-regulation by hypermethylation in genes likely to result in HCC metabolic reprogramming ( ALB , APOB , and CPS1 ) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1. Multiplex molecular profiling of human hepatocellular carcinoma patients provides insight into subtype characteristics and points toward key pathways to target therapeutically.
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            Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-analysis

            Kristina Tzartzeva, Joseph Obi, Nicole Rich … (2018)
            Background & Aims Society guidelines differ in their recommendations for surveillance to detect early-stage hepatocellular carcinoma (HCC) in patients with cirrhosis. We compared the performance of surveillance imaging, with or without alpha fetoprotein (AFP), for early detection of HCC in patients with cirrhosis Methods Two reviewers searched MEDLINE and SCOPUS from January 1990 through August 2016 to identify published sensitivity and specificity of surveillance strategies for overall and early detection of HCC. Pooled estimates were calculated and compared using the DerSimonian and Laird method for a random effects model. The study was conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. Results Thirty-two studies (comprising 13367 patients) characterized sensitivity of imaging with or without AFP measurement for detection of HCC in patients with cirrhosis. Ultrasound detected any stage HCC with 84% sensitivity (95% CI, 76%–92%), but early-stage HCC with only 47% sensitivity (95% CI, 33%–61%). In studies comparing ultrasound with vs without AFP measurement, ultrasound detected any stage HCC with a lower level of sensitivity than ultrasound plus AFP measurement (relative risk [RR], 0.88; 95% CI, 0.83–0.93) and early-stage HCC with a lower level of sensitivity than ultrasound plus AFP measurement (RR, 0.81; 95% CI, 0.71–0.93). However, ultrasound alone detected HCC with a higher level of specificity than ultrasound plus AFP measurement (RR, 1.08; 95% CI, 1.05–1.09). Ultrasound with vs without AFP detected early-stage HCC with 63% sensitivity (95% CI, 48%–75%) and 45% sensitivity (95% CI, 30%–62%), respectively ( P =.002). Only 4 studies evaluated computed tomography or magnetic resonance image-based surveillance, which detected HCC with 84% sensitivity (95% CI, 70%–92%). Conclusions In a meta-analysis of publications, we found ultrasound alone to detect early-stage HCC with a low level of sensitivity in patients with cirrhosis. Addition of AFP to ultrasound analysis significantly increases the sensitivity of HCC detection in clinical practice.
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              Randomized controlled trial of screening for hepatocellular carcinoma.

              Bo-Heng Zhang, Bing-Hui Yang, Zhao-You Tang (2004)
              Screening for hepatocellular carcinoma (HCC) has been conducted for over 20 years, but there is no conclusive evidence that screening may reduce HCC mortality. The aim of this study was to assess the effect of screening on HCC mortality in people at increased risk. This study included 18,816 people, aged 35-59 years with hepatitis B virus infection or a history of chronic hepatitis in urban Shanghai, China. Participants were randomly allocated to a screening (9,373) or control (9,443) group. Controls received no screening and continued to use health-care facilities. Screening group participants were invited to have an AFP test and ultrasonography examination every 6 months. Screening was stopped in December 1997; by that time screening group participants had been offered five to ten times. All participants were followed up until December 1998. The primary outcome measure was HCC mortality. The screened group completed 58.2 percent of the screening offered. When the screening group was compared to the control group, the number of HCC was 86 versus 67; subclinical HCC being 52 (60.5%) versus 0; small HCC 39 (45.3%) versus 0; resection achieved 40 (46.5%) versus 5 (7.5%); 1-, 3,-, and 5-year survival rate 65.9%, 52.6%, 46.4% versus 31.2%, 7.2%, 0, respectively. Thirty-two people died from HCC in the screened group versus 54 in the control group, and the HCC mortality rate was significantly lower in the screened group than in controls, being 83.2/100,000 and 131.5/100,000, respectively, with a mortality rate ratio of 0.63 (95%CI 0.41-0.98). Our finding indicated that biannual screening reduced HCC mortality by 37%.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cells
                Journal ID (iso-abbrev): Cells
                Journal ID (publisher-id): cells
                Title: Cells
                Publisher: MDPI
                ISSN (Electronic): 2073-4409
                Publication date (Electronic): 01 June 2020
                Publication date Collection: June 2020
                Volume: 9
                Issue: 6
                Electronic Location Identifier: 1370
                Affiliations
                [1 ]Hepatology and Liver Transplant Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629AHJ Buenos Aires, Argentina; fpinerof@ 123456cas.austral.edu.ar
                [2 ]Latin American Liver Research Educational and Awareness Network (LALREAN), B1629AHJ Buenos Aires, Argentina
                [3 ]Liver Unit, Hospital Privado de Rosario, 2000 Rosario, Santa Fe, Argentina; mdirchwolf@ 123456outlook.com
                [4 ]Division of Gastroenterology and Hepatology, University of São Paulo School of Medicine, 05403-000 São Paulo, Brazil
                Author notes
                [* ]Correspondence: mgpessoa@ 123456usp.br ; Tel.: +55-11-2661-3340
                Author information
                https://orcid.org/0000-0002-9528-2279
                Article
                Publisher ID: cells-09-01370
                DOI: 10.3390/cells9061370
                PMC ID: 7349517
                PubMed ID: 32492896
                SO-VID: b515c6b7-66a2-45c1-b393-8c30af7a7dab
                Copyright © © 2020 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 05 May 2020
                Date accepted : 28 May 2020
                Categories
                Subject: Review

                Keywords: liver cancer,biological,markers
                Data availability:
                Keywords: liver cancer, biological, markers

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