Circulating predictive and diagnostic biomarkers for hepatitis B virus-associated hepatocellular carcinoma

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Abstract

Chronic hepatitis B virus (HBV) infected patients have an almost 100-fold increased risk to develop hepatocellular carcinoma (HCC). HCC is the fifth most common and third most deadly cancer worldwide. Up to 50% of newly diagnosed HCC cases are attributed to HBV infection. Early detection improves survival and can be achieved through regular screening. Six-monthly abdominal ultrasound, either alone or in combination with alpha-fetoprotein serum levels, has been widely endorsed for this purpose. Both techniques however yield limited diagnostic accuracy, which is not improved when they are combined. Alternative circulating or histological markers to predict or diagnose HCC are therefore urgently needed. Recent advances in systems biology technologies have enabled the identification of several new putative circulating biomarkers. Although results from studies assessing combinations of these biomarkers are promising, evidence for their clinical utility remains low. In addition, most of the studies conducted so far show limitations in design. Attention must be paid for instance to different ethnicities and different etiologies when studying biomarkers for hepatocellular carcinoma. This review provides an overview on the current understandings and recent progress in the field of diagnostic and predictive circulating biomarkers for hepatocellular carcinoma in chronically infected HBV patients and discusses the future prospects.

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Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study

Joong-Won Park, Minshan Chen, Massimo Colombo … (2015)

Background & Aims Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. The global HCC BRIDGE study was a multiregional, large-scale, longitudinal cohort study undertaken to improve understanding of real-life management of patients with HCC, from diagnosis to death. Methods Data were collected retrospectively from January 2005 to September 2012 by chart reviews of eligible patients newly diagnosed with HCC at participating institutions. Results Forty-two sites in 14 countries contributed final data for 18 031 patients. Asia accounted for 67% of patients, Europe for 20% and North America for 13%. As expected, the most common risk factor was hepatitis C virus in North America, Europe and Japan, and hepatitis B virus in China, South Korea and Taiwan. The most common Barcelona Clinic Liver Cancer stage at diagnosis was C in North America, Europe, China and South Korea, and A in Taiwan and Japan. Across all stages, first HCC treatment was most frequently transarterial chemoembolization in North America, Europe, China and South Korea, percutaneous ethanol injection or radiofrequency ablation in Japan and resection in Taiwan. Survival from first HCC treatment varied significantly by region, with median overall survival not reached for Taiwan and 60, 33, 31, 24 and 23 months for Japan, North America, South Korea, Europe and China respectively (P < 0.0001). Conclusions Initial results from the BRIDGE study confirm previously reported regional trends in patient demographic characteristics and HCC risk factors, document the heterogeneity of treatment approaches across regions/countries and underscore the need for earlier HCC diagnosis worldwide.

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miR-21-mediated tumor growth.

M-L Si, S Zhu, H. Wu … (2007)

MicroRNAs (miRNAs) are approximately 22 nucleotide non-coding RNA molecules that regulate gene expression post-transcriptionally. Although aberrant expression of miRNAs in various human cancers suggests a role for miRNAs in tumorigenesis, it remains largely unclear as to whether knockdown of a specific miRNA affects tumor growth. In this study, we profiled miRNA expression in matched normal breast tissue and breast tumor tissues by TaqMan real-time polymerase chain reaction miRNA array methods. Consistent with previous findings, we found that miR-21 was highly overexpressed in breast tumors compared to the matched normal breast tissues among 157 human miRNAs analysed. To better evaluate the role of miR-21 in tumorigenesis, we transfected breast cancer MCF-7 cells with anti-miR-21 oligonucleotides and found that anti-miR-21 suppressed both cell growth in vitro and tumor growth in the xenograft mouse model. Furthermore, this anti-miR-21-mediated cell growth inhibition was associated with increased apoptosis and decreased cell proliferation, which could be in part owing to downregulation of the antiapoptotic Bcl-2 in anti-miR-21-treated tumor cells. Together, these results suggest that miR-21 functions as an oncogene and modulates tumorigenesis through regulation of genes such as bcl-2 and thus, it may serve as a novel therapeutic target.

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Gene expression in fixed tissues and outcome in hepatocellular carcinoma.

Yujin Hoshida, Augusto Villanueva, Masahiro Kobayashi … (2008)

It is a challenge to identify patients who, after undergoing potentially curative treatment for hepatocellular carcinoma, are at greatest risk for recurrence. Such high-risk patients could receive novel interventional measures. An obstacle to the development of genome-based predictors of outcome in patients with hepatocellular carcinoma has been the lack of a means to carry out genomewide expression profiling of fixed, as opposed to frozen, tissue. We aimed to demonstrate the feasibility of gene-expression profiling of more than 6000 human genes in formalin-fixed, paraffin-embedded tissues. We applied the method to tissues from 307 patients with hepatocellular carcinoma, from four series of patients, to discover and validate a gene-expression signature associated with survival. The expression-profiling method for formalin-fixed, paraffin-embedded tissue was highly effective: samples from 90% of the patients yielded data of high quality, including samples that had been archived for more than 24 years. Gene-expression profiles of tumor tissue failed to yield a significant association with survival. In contrast, profiles of the surrounding nontumoral liver tissue were highly correlated with survival in a training set of tissue samples from 82 Japanese patients, and the signature was validated in tissues from an independent group of 225 patients from the United States and Europe (P=0.04). We have demonstrated the feasibility of genomewide expression profiling of formalin-fixed, paraffin-embedded tissues and have shown that a reproducible gene-expression signature correlated with survival is present in liver tissue adjacent to the tumor in patients with hepatocellular carcinoma. Copyright 2008 Massachusetts Medical Society.

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Author and article information

Journal

Journal ID (nlm-ta): World J Gastroenterol

Journal ID (iso-abbrev): World J. Gastroenterol

Journal ID (publisher-id): WJG

Title: World Journal of Gastroenterology

Publisher: Baishideng Publishing Group Inc

ISSN (Print): 1007-9327

ISSN (Electronic): 2219-2840

Publication date (Print): 7 October 2016

Publication date (Electronic): 7 October 2016

Volume: 22

Issue: 37

Pages: 8271-8282

Affiliations

Stijn Van Hees, Peter Michielsen, Thomas Vanwolleghem, Department of Gastroenterology and Hepatology, Antwerp University Hospital, 2650 Edegem, Belgium

Stijn Van Hees, Peter Michielsen, Thomas Vanwolleghem, Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, 2610 Antwerp, Belgium

Author notes

Author contributions: Van Hees S and Vanwolleghem T conceptualized the manuscript; Van Hees S wrote the manuscript; all authors contributed to the critical revision and editing of the paper; Michielsen P and Vanwolleghem T approved the final version.

Supported by Foundation Against Cancer Belgium, No. 2014-087.

Correspondence to: Thomas Vanwolleghem, MD, PhD, Department of Gastroenterology and Hepatology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium. thomas.vanwolleghem@ 123456uza.be

Telephone: +32-3-8213853 Fax: +32-3-8214478

Article

Other ID: jWJG.v22.i37.pg8271

DOI: 10.3748/wjg.v22.i37.8271

PMC ID: 5055858

PubMed ID: 27729734

SO-VID: 7913e3a5-919b-4c1a-bd9b-c31e6723f183

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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

History

Date received : 26 April 2016

Date revision received : 18 July 2016

Date accepted : 5 August 2016

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Circulating predictive and diagnostic biomarkers for hepatitis B virus-associated hepatocellular carcinoma

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Point-Of-Care Testing for Hepatitis

Most cited references 119

Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study

miR-21-mediated tumor growth.

Gene expression in fixed tissues and outcome in hepatocellular carcinoma.

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