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Circulating Cell-Free DNA in Hepatocellular Carcinoma: Current Insights and Outlook

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Circulating Cell-Free DNA in Hepatocellular Carcinoma: Current Insights and Outlook View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by edoc REVIEW published: 26 March 2018 doi: 10.3389/fmed.2018.00078 Circulating Cell-Free DNA in Hepatocellular Carcinoma: Current Insights and Outlook Charlotte K. Y. Ng1,2*, Giovan Giuseppe Di Costanzo3, Luigi M. Terracciano1 and Salvatore Piscuoglio1* 1 Institute of Pathology, University Hospital Basel, Basel, Switzerland, 2 Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland, 3 Department of Transplantation – Liver Unit, Cardarelli Hospital, Naples, Italy Over the past decade, the advancements in massively parallel sequencing have pro- vided a new paradigm in biomedical research to uncover the genetic basis of human diseases. Integration of ‘omics information has begun transforming clinical management of cancer patients in terms of diagnostics and treatment options, giving rise to the era of precision medicine. Currently, nucleic acids for molecular profiling for patients diagnosed with hepatocellular carcinoma (HCC) are typically obtained from resected tumor mate- rials or transplanted neoplastic liver and occasionally from biopsies. Given the intrinsic risks associated with such invasive procedures, circulating cell-free DNA (cfDNA) has been proposed as an alternative source for tumor DNA. Circulating cfDNA is a type of Edited by: cell-free nucleic acid that derives from apoptotic, necrotic, as well as living eukaryotic Venancio Avancini Alves, University of São Paulo, Brazil cells. Importantly, the detection of abnormal forms of circulating cfDNA that originate Reviewed by: from cancer cells provides a new tool for cancer detection, disease monitoring, and Fernando Schmitt, molecular profiling. Currently, cfDNA is beginning to be adopted into clinical practice Universidade do Porto, Portugal Marco Volante, as a non-invasive tool to monitor disease by tracking the evolution of disease-specific Università degli Studi di Torino, Italy genetic alterations in several major cancer types. Moreover, cfDNA is demonstrating *Correspondence: potential clinical value as a surrogate to assess the molecular makeup of tumors and Charlotte K. Y. Ng to overcome the sampling biases inherent to intra-tumor genetic heterogeneity, espe- [email protected]; Salvatore Piscuoglio cially in the metastatic setting. With the improvements in ‘omics and molecular biology [email protected] techniques, coupled with the increasing understanding in the molecular pathogenesis of cancer, it can be anticipated that the detection and analysis of cfDNA will become more Specialty section: This article was submitted to specific and sensitive and thus enable cfDNA analysis to be used as a diagnostic aid in Pathology, patients with early-stage disease and perhaps even in a screening setting. In this review, a section of the journal we provide an overview of the latest findings on the role and potential utility of cfDNA Frontiers in Medicine analysis in the diagnosis, management, and screening of HCC. Received: 24 December 2017 Accepted: 08 March 2018 Keywords: cell-free DNA, circulating tumor DNA, hepatocellular carcinoma, liquid biopsy, somatic mutations, Published: 26 March 2018 copy number alterations, methylation Citation: Ng CKY, Di Costanzo GG, Terracciano LM and Piscuoglio S (2018) Circulating Cell-Free DNA in REVIEW CRITERIA Hepatocellular Carcinoma: Current Insights and Outlook. Review of the literature was performed in English using the PubMed database. Search terms used Front. Med. 5:78. included “hepatocellular carcinoma,” “liver cancer,” “circulating cell free DNA,” “circulating tumor doi: 10.3389/fmed.2018.00078 DNA,” “plasma,” “serum,” and “liquid biopsy.” Frontiers in Medicine | www.frontiersin.org 1 March 2018 | Volume 5 | Article 78 Ng et al. Liquid Biopsy in HCC INTRODUCTION status of circulating cell-free DNA (cfDNA) as a “liquid biopsy” in HCC, and discussed the outlook of how circulating cfDNA may Over the past decade, the advancements in next-generation address some of the challenges in the clinic. sequencing (NGS) and high-throughput omics profiling have provided a new paradigm in biomedical research to uncover the epi/genetic basis of human diseases. Integration of omics CLINICAL CHALLENGES IN LIVER information has begun to transform clinical management of CANCER cancer patients in terms of diagnostics, prevention, and treatment options, giving rise to the era of precision medicine. Compared to In the context of precision medicine, one of the biggest chal- cancer types such as those of the breasts and the lungs, precision lenges in HCC clinical management is the frequent lack of tumor medicine for hepatocellular carcinoma (HCC) patients is lagging tissue for molecular profiling. Tumor materials may be obtained behind, owing to a number of HCC-specific challenges in clinical during resection and/or transplantation. However, these practice and the lack of treatment options. procedures are restricted to patients with early-stage, limited Hepatocellular carcinoma accounts for >90% of liver can- HCC (11). Unlike most other solid tumor types, the diagnosis cers and was responsible for an estimated 782,000 new cancer of HCC does not always require the histopathologic analysis of cases and nearly 746,000 deaths in 2012 (1). While HCC is the tumor tissue. This is particularly true for patients with a known sixth most common cause of cancer worldwide, it is the third background of cirrhosis. In cirrhotic patients, HCC is frequently most common cause of cancer deaths and has one of the high- diagnosed on radiology alone or with serum alpha-fetoprotein est mortality-to-incidence ratios (2). HCC usually occurs in (AFP) levels (11). Consequently, tumor materials for genetic cirrhotic livers, and the epidemiology of HCC shows marked profiling are unavailable for many unresectable HCC patients. variations between geographical regions and racial groups (3). Indeed, molecular profiling studies of HCC tumor tissues are In sub-Saharan Africa and south-east Asia, hepatitis B virus frequently biased toward resectable tumors (12–23). Moreover, (HBV) chronic infection is endemic and accounts for the major- biopsy and surgical intervention are invasive procedures, and ity of HCCs diagnosed (2). In Western populations, the rising thus longitudinal sampling for the purpose of disease monitor- incidence of HCC is in part driven by the increasing prevalence ing is clinically not feasible nor warranted in nearly all cases. of chronic liver diseases associated with hepatitis C virus (HCV) An alternative source of DNA for molecular profiling would be infection, alcohol consumption, diabetes, obesity, and non- highly desirable. alcoholic fatty liver disease (2, 4, 5). Other known risk factors of Early detection from screening programs has been reported HCC include hereditary diseases such as hemochromatosis and to confer a survival benefit in HCC patients (24, 25). Currently, α-1-antitrypsin deficiency, exposure to aflatoxin B1 through the most widely used blood-based biomarker is serum AFP. dietary consumption, smoking, and the male gender (2). The The clinical utility of AFP for diagnosis, even in the screening 5-year cumulative risk for HCC in patients with cirrhosis ranges setting of high-risk patients, is limited by its lack of sensitiv- between 5 and 30%, depending on the cause (with the highest ity and specificity. In fact, a substantial proportion of HCC risk among those infected with HCV), region or ethnic group patients do not display elevated serum AFP levels, while (17% in the United States and 30% in Japan), and stage of cirrho- patients with chronic liver disease may also show elevated sis (with the highest risk among patients with decompensated levels (26). Indeed, AFP is not currently recommended as the disease) (6). sole diagnostic marker (11). The stagnating prognosis of HCC is contributed in part by Like virtually all solid tumors, variable levels of intra-tumor the limited treatment options. For early-stage HCC, curative genetic heterogeneity with branched and parallel evolutionary treatment options involve resection and/or liver transplantation, patterns have been detected in HCC patients (27, 28). Genetic with >50% 5-year overall survival. By contrast, for patients with diversity appears to show spatial organization, with intrahepatic late-stage unresectable disease or ineligible for transplantation, metastases showing rapid diversification at the distant site (28). 5-year overall survival is <10%. Treatment options may include HCC may also metastasize to distant organs, most frequently to transarterial chemoembolization (TACE) and radiofrequency the lungs, the lymph nodes, bone, and the adrenal glands. To add ablation. In terms of systemic treatment, the multi-kinase inhibitor to the complexity, recurrent or multifocal HCC may represent sorafenib is the only first-line agent for HCC, but it only extends intrahepatic metastasis, in which the malignant cells are dissemi- survival by 2.8 months in late-stage patients (7). Regorafenib (a nated from a single primary tumor or may represent independent multi-kinase inhibitor) (8) and nivolumab (a PD-1 inhibitor) (9) (multi-centric) tumors (29). Clinical distinction between these were recently approved as second-line treatment in patients who two entities is important as intrahepatic metastases are likely to progressed on sorafenib, bringing the total number of approved be more poorly differentiated and aggressive. Molecular analysis systemic agents to
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