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      Cell-free circulating mitochondrial DNA content and risk of hepatocellular carcinoma in patients with chronic HBV infection

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          Abstract

          Recent studies have demonstrated a potential link between circulating cell-free mitochondrial DNA (mtDNA) content and cancers. However, there is no study evaluating the association between circulating mtDNA as a non-invasive marker of hepatocellular carcinoma (HCC) risk. We conducted a nested case-control study to determine circulating mtDNA content in serum samples from 116 HBV-related HCC cases and 232 frequency-matched cancer-free HBV controls, and evaluate the retrospective association between mtDNA content and HCC risk using logistic regression and their temporal relationship using a mixed effects model. HCC cases had significantly lower circulating mtDNA content than controls (1.06 versus 2.47, P = 1.7 × 10 −5). Compared to HBV patients with higher mtDNA content, those with lower mtDNA content had a significantly increased risk of HCC with an odds ratio (OR) of 2.19 (95% confidence interval [CI] 1.28–3.72, P = 0.004). Quartile analyses revealed a significant dose-dependent effect ( P trend = 0.001) for this association. In a pilot longitudinal sub-cohort of 14 matched cases-control pairs, we observed a trend of dramatically decreased mtDNA content in cases and slightly decreased mtDNA content in controls, with a significant interaction of case-control status with time ( P interaction = 0.049). Our findings suggest that circulating mtDNA is a potential novel non-invasive biomarker of HCC risk in HBV patients.

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          Most cited references30

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          On the origin of cancer cells.

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            Decoding cell death signals in liver inflammation.

            Inflammation can be either beneficial or detrimental to the liver, depending on multiple factors. Mild (i.e., limited in intensity and destined to resolve) inflammatory responses have indeed been shown to exert consistent hepatoprotective effects, contributing to tissue repair and promoting the re-establishment of homeostasis. Conversely, excessive (i.e., disproportionate in intensity and permanent) inflammation may induce a massive loss of hepatocytes and hence exacerbate the severity of various hepatic conditions, including ischemia-reperfusion injury, systemic metabolic alterations (e.g., obesity, diabetes, non-alcoholic fatty liver disorders), alcoholic hepatitis, intoxication by xenobiotics and infection, de facto being associated with irreversible liver damage, fibrosis, and carcinogenesis. Both liver-resident cells (e.g., Kupffer cells, hepatic stellate cells, sinusoidal endothelial cells) and cells that are recruited in response to injury (e.g., monocytes, macrophages, dendritic cells, natural killer cells) emit pro-inflammatory signals including - but not limited to - cytokines, chemokines, lipid messengers, and reactive oxygen species that contribute to the apoptotic or necrotic demise of hepatocytes. In turn, dying hepatocytes release damage-associated molecular patterns that-upon binding to evolutionary conserved pattern recognition receptors-activate cells of the innate immune system to further stimulate inflammatory responses, hence establishing a highly hepatotoxic feedforward cycle of inflammation and cell death. In this review, we discuss the cellular and molecular mechanisms that account for the most deleterious effect of hepatic inflammation at the cellular level, that is, the initiation of a massive cell death response among hepatocytes. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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              Circulating nucleic acids (CNAs) and cancer--a survey.

              It has been known for decades that it is possible to detect small amounts of extracellular nucleic acids in plasma and serum of healthy and diseased human beings. The unequivocal proof that part of these circulating nucleic acids (CNAs) is of tumor origin, initiated a surge of studies which confirmed and extended the original observations. In the past few years many experiments showed that tumor-associated alterations can be detected at the DNA and RNA level. At the DNA level the detection of point mutations, microsatellite alterations, chromosomal alterations, i.e. inversion and deletion, and hypermethylation of promoter sequences were demonstrated. At the RNA level the overexpression of tumor-associated genes was shown. These observations laid the foundation for the development of assays for an early detection of cancer as well as for other clinical means.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                11 April 2016
                2016
                : 6
                : 23992
                Affiliations
                [1 ]Division of Population Science, Department of Medical Oncology , Thomas Jefferson University, Philadelphia, PA 19107, USA
                [2 ]Liver Disease Prevention Center, Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University , Philadelphia, PA 19107, USA
                [3 ]Institute of Pharmacy, Pharmaceutical College, Henan University , Kaifeng, Henan 475004, China
                [4 ]Department of Environmental Health, School of Public Health, Nantong University , Nantong, Jiangsu 226000, China
                [5 ]Center for Human Genetics Research, Department of Molecular Physiology & Biophysics, Vanderbilt University , Nashville, TN 37232, USA
                [6 ]Experimental Teaching Center, School of Basic Medicine, Fourth Military Medical University , Xi’an, 710032, China
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                srep23992
                10.1038/srep23992
                4827061
                27063412
                20d16262-a793-4b27-a276-e732ef3a964f
                Copyright © 2016, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 02 October 2015
                : 18 March 2016
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