{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:25:03Z","timestamp":1760235903728,"version":"build-2065373602"},"reference-count":62,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,11]],"date-time":"2021-10-11T00:00:00Z","timestamp":1633910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010089","name":"JGW Patterson Foundation","doi-asserted-by":"publisher","award":["RES\/0190\/7948","RES\/0260\/0217"],"award-info":[{"award-number":["RES\/0190\/7948","RES\/0260\/0217"]}],"id":[{"id":"10.13039\/100010089","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C18342\/A23390; C9380\/A26813"],"award-info":[{"award-number":["C18342\/A23390; C9380\/A26813"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010897","name":"Newton Fund","doi-asserted-by":"publisher","award":["RES\/0280\/0076"],"award-info":[{"award-number":["RES\/0280\/0076"]}],"id":[{"id":"10.13039\/100010897","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Newcastle upon Tyne Hospitals NHS Charity","award":["RES\/0280\/0080"],"award-info":[{"award-number":["RES\/0280\/0080"]}]},{"name":"NHMRC Investigator Grant","award":["GNT1173711"],"award-info":[{"award-number":["GNT1173711"]}]},{"DOI":"10.13039\/501100007155","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MC_UU12014\/2"],"award-info":[{"award-number":["MC_UU12014\/2"]}],"id":[{"id":"10.13039\/501100007155","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Hepatitis C virus (HCV) is a common cause of hepatocellular carcinoma (HCC). The activation and mutagenic consequences of L1 retrotransposons in virus-associated-HCC have been documented. However, the direct influence of HCV upon L1 elements is unclear, and is the focus of the present study. L1 transcript expression was evaluated in a publicly available liver tissue RNA-seq dataset from patients with chronic HCV hepatitis (CHC), as well as healthy controls. L1 transcript expression was significantly higher in CHC than in controls. L1orf1p (a L1 encoded protein) expression was observed in six out of 11 CHC livers by immunohistochemistry. To evaluate the influence of HCV on retrotransposition efficiency, in vitro engineered-L1 retrotransposition assays were employed in Huh7 cells in the presence and absence of an HCV replicon. An increased retrotransposition rate was observed in the presence of replicating HCV RNA, and persisted in cells after viral clearance due to sofosbuvir (PSI7977) treatment. Increased retrotransposition could be due to dysregulation of the DNA-damage repair response, including homologous recombination, due to HCV infection. Altogether these data suggest that L1 expression can be activated before oncogenic transformation in CHC patients, with HCV-upregulated retrotransposition potentially contributing to HCC genomic instability and a risk of transformation that persists post-viral clearance.<\/jats:p>","DOI":"10.3390\/cancers13205079","type":"journal-article","created":{"date-parts":[[2021,10,11]],"date-time":"2021-10-11T09:16:42Z","timestamp":1633943802000},"page":"5079","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["HCV Activates Somatic L1 Retrotransposition\u2014A Potential Hepatocarcinogenesis Pathway"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7733-8507","authenticated-orcid":false,"given":"Praveen D.","family":"Sudhindar","sequence":"first","affiliation":[{"name":"Newcastle University Centre for Cancer, Biosciences Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Wainwright","sequence":"additional","affiliation":[{"name":"Newcastle University Centre for Cancer, Biosciences Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Santu","family":"Saha","sequence":"additional","affiliation":[{"name":"Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Howarth","sequence":"additional","affiliation":[{"name":"Newcastle University Centre for Cancer, Biosciences Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1967-0421","authenticated-orcid":false,"given":"Misti","family":"McCain","sequence":"additional","affiliation":[{"name":"Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3285-3991","authenticated-orcid":false,"given":"Yvonne","family":"Bury","sequence":"additional","affiliation":[{"name":"Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sweta S.","family":"Saha","sequence":"additional","affiliation":[{"name":"Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stuart","family":"McPherson","sequence":"additional","affiliation":[{"name":"The Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Heaton NE7 7DN, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen","family":"Reeves","sequence":"additional","affiliation":[{"name":"Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"The Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Heaton NE7 7DN, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4600-2047","authenticated-orcid":false,"given":"Arvind H.","family":"Patel","sequence":"additional","affiliation":[{"name":"MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow G61 1QH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geoffrey J.","family":"Faulkner","sequence":"additional","affiliation":[{"name":"Mater Research Institute, University of Queensland, Woolloongabba, QLD 4102, Australia"},{"name":"Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Lunec","sequence":"additional","affiliation":[{"name":"Newcastle University Centre for Cancer, Biosciences Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9348-6198","authenticated-orcid":false,"given":"Ruchi","family":"Shukla","sequence":"additional","affiliation":[{"name":"Newcastle University Centre for Cancer, Biosciences Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.jhep.2019.08.025","article-title":"Epidemiology and surveillance for hepatocellular carcinoma: New trends","volume":"72","author":"Singal","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1056\/NEJMp1400986","article-title":"Curing chronic hepatitis c\u2014The arc of a medical triumph","volume":"370","author":"Chung","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Rinaldi, L., Nevola, R., Franci, G., Perrella, A., Corvino, G., Marrone, A., Berretta, M., Morone, M.V., Galdiero, M., and Giordano, M. (2020). Risk of hepatocellular carcinoma after hcv clearance by direct-acting antivirals treatment predictive factors and role of epigenetics. Cancers, 12.","DOI":"10.3390\/cancers12061351"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.jhep.2020.10.016","article-title":"Hcc surveillance after svr in patients with f3\/f4 fibrosis","volume":"74","author":"Ioannou","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.jhep.2016.04.008","article-title":"Unexpected high rate of early tumor recurrence in patients with hcv-related hcc undergoing interferon-free therapy","volume":"65","author":"Reig","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/j.cmi.2016.08.025","article-title":"Hepatitis c virus: Life cycle in cells, infection and host response, and analysis of molecular markers influencing the outcome of infection and response to therapy","volume":"22","author":"Dustin","year":"2016","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_8","first-page":"1409582","article-title":"Flaviviridae viruses and oxidative stress: Implications for viral pathogenesis","volume":"2019","author":"Zhang","year":"2019","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1245\/s10434-006-9049-1","article-title":"Predictive power of biomarkers of oxidative stress and inflammation in patients with hepatitis c virus-associated hepatocellular carcinoma","volume":"14","author":"Maki","year":"2007","journal-title":"Ann. Surg. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9012580","DOI":"10.1155\/2016\/9012580","article-title":"Hcv and oxidative stress: Implications for hcv life cycle and hcv-associated pathogenesis","volume":"2016","author":"Medvedev","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Chu, J.Y.K., and Ou, J.J. (2021). Autophagy in hcv replication and protein trafficking. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031089"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Chan, S.T., and Ou, J.J. (2017). Hepatitis c virus-induced autophagy and host innate immune response. Viruses, 9.","DOI":"10.3390\/v9080224"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6985","DOI":"10.4049\/jimmunol.1000618","article-title":"Hepatitis c virus inhibits DNA damage repair through reactive oxygen and nitrogen species and by interfering with the atm-nbs1\/mre11\/rad50 DNA repair pathway in monocytes and hepatocytes","volume":"185","author":"Machida","year":"2010","journal-title":"J. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e00178-18","DOI":"10.1128\/JVI.00178-18","article-title":"Nonstructural protein 5a impairs DNA damage repair: Implications for hepatitis c virus-mediated hepatocarcinogenesis","volume":"92","author":"Nguyen","year":"2018","journal-title":"J. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ryan, E.L., Hollingworth, R., and Grand, R.J. (2016). Activation of the DNA damage response by rna viruses. Biomolecules, 6.","DOI":"10.3390\/biom6010002"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1038\/onc.2016.340","article-title":"A pre-neoplastic epigenetic field defect in hcv-infected liver at transcription factor binding sites and polycomb targets","volume":"36","author":"Wijetunga","year":"2017","journal-title":"Oncogene"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.2174\/13816128113199990533","article-title":"Epigenetic mechanism involved in the hbv\/hcv-related hepatocellular carcinoma tumorigenesis","volume":"20","author":"Rongrui","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1053\/j.gastro.2019.02.038","article-title":"Hcv-induced epigenetic changes associated with liver cancer risk persist after sustained virologic response","volume":"156","author":"Hamdane","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Perez, S., Kaspi, A., Domovitz, T., Davidovich, A., Lavi-Itzkovitz, A., Meirson, T., Alison Holmes, J., Dai, C.Y., Huang, C.F., and Chung, R.T. (2019). Hepatitis c virus leaves an epigenetic signature post cure of infection by direct-acting antivirals. PLoS Genet., 15.","DOI":"10.1371\/journal.pgen.1008181"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1053\/j.gastro.2013.10.056","article-title":"Hepatitis virus infection affects DNA methylation in mice with humanized livers","volume":"146","author":"Okamoto","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.cell.2013.02.032","article-title":"Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma","volume":"153","author":"Shukla","year":"2013","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/s41588-019-0562-0","article-title":"Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by line-1 retrotransposition","volume":"52","author":"Alvarez","year":"2020","journal-title":"Nat. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1101\/gr.226993.117","article-title":"L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis","volume":"28","author":"Schauer","year":"2018","journal-title":"Genome Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1186\/s13148-019-0733-y","article-title":"DNA methylation of individual repetitive elements in hepatitis c virus infection-induced hepatocellular carcinoma","volume":"11","author":"Zheng","year":"2019","journal-title":"Clin. Epigenetics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1126\/science.1222077","article-title":"Landscape of somatic retrotransposition in human cancers","volume":"337","author":"Lee","year":"2012","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1128\/JVI.05452-11","article-title":"Conserved glycine 33 residue in flexible domain i of hepatitis c virus core protein is critical for virus infectivity","volume":"86","author":"Angus","year":"2012","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"29487","DOI":"10.1038\/srep29487","article-title":"Exploration of acetanilide derivatives of 1-(omega-phenoxyalkyl)uracils as novel inhibitors of hepatitis c virus replication","volume":"6","author":"Magri","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/j.cell.2019.02.050","article-title":"Genome-wide de novo l1 retrotransposition connects endonuclease activity with replication","volume":"177","author":"Flasch","year":"2019","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/S0092-8674(00)81998-4","article-title":"High frequency retrotransposition in cultured mammalian cells","volume":"87","author":"Moran","year":"1996","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10286","DOI":"10.1038\/ncomms10286","article-title":"Reprogramming triggers endogenous l1 and alu retrotransposition in human induced pluripotent stem cells","volume":"7","author":"Klawitter","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Bradbury, A., O\u2019Donnell, R., Drew, Y., Curtin, N.J., and Sharma Saha, S. (2020). Characterisation of ovarian cancer cell line nih-ovcar3 and implications of genomic, transcriptomic, proteomic and functional DNA damage response biomarkers for therapeutic targeting. Cancers, 12.","DOI":"10.3390\/cancers12071939"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/bjc.2017.433","article-title":"Targeting negative regulation of p53 by mdm2 and wip1 as a therapeutic strategy in cutaneous melanoma","volume":"118","author":"Wu","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1128\/MCB.21.4.1429-1439.2001","article-title":"Human l1 retrotransposition: Cis preference versus trans complementation","volume":"21","author":"Wei","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/0092-8674(93)90078-5","article-title":"Reverse transcription of r2bm rna is primed by a nick at the chromosomal target site: A mechanism for non-ltr retrotransposition","volume":"72","author":"Luan","year":"1993","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/S0092-8674(00)81997-2","article-title":"Human l1 retrotransposon encodes a conserved endonuclease required for retrotransposition","volume":"87","author":"Feng","year":"1996","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/nature05560","article-title":"Endonuclease-independent line-1 retrotransposition at mammalian telomeres","volume":"446","author":"Morrish","year":"2007","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s13100-016-0070-z","article-title":"Restricting retrotransposons: A review","volume":"7","author":"Goodier","year":"2016","journal-title":"Mob. DNA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1016\/j.jmb.2006.01.089","article-title":"The human line-1 retrotransposon creates DNA double-strand breaks","volume":"357","author":"Gasior","year":"2006","journal-title":"J. Mol. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"20382","DOI":"10.1073\/pnas.1100273108","article-title":"Ataxia telangiectasia mutated (atm) modulates long interspersed element-1 (l1) retrotransposition in human neural stem cells","volume":"108","author":"Coufal","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/s41594-020-0374-z","article-title":"Brca1 and s phase DNA repair pathways restrict line-1 retrotransposition in human cells","volume":"27","author":"Mita","year":"2020","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Rundle, S., Bradbury, A., Drew, Y., and Curtin, N.J. (2017). Targeting the atr-chk1 axis in cancer therapy. Cancers, 9.","DOI":"10.3390\/cancers9050041"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Schobel, A., Nguyen-Dinh, V., Schumann, G.G., and Herker, E. (2021). Hepatitis c virus infection restricts human line-1 retrotransposition in hepatoma cells. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009496"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4340","DOI":"10.1038\/s41388-019-0726-5","article-title":"Latent infection with kaposi\u2019s sarcoma-associated herpesvirus enhances retrotransposition of long interspersed element-1","volume":"38","author":"Nakayama","year":"2019","journal-title":"Oncogene"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"8454","DOI":"10.1093\/nar\/gky688","article-title":"Hiv-1 vpr and p21 restrict line-1 mobility","volume":"46","author":"Kawano","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/1742-4690-10-83","article-title":"Viral protein r of human immunodeficiency virus type-1 induces retrotransposition of long interspersed element-1","volume":"10","author":"Iijima","year":"2013","journal-title":"Retrovirology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"13307","DOI":"10.1128\/JVI.02257-13","article-title":"Line-1 retrotransposable element DNA accumulates in hiv-1-infected cells","volume":"87","author":"Jones","year":"2013","journal-title":"J. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"10191","DOI":"10.1074\/jbc.M114.612374","article-title":"Type i interferon controls propagation of long interspersed element-1","volume":"290","author":"Yu","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Dai, L., Huang, Q., and Boeke, J.D. (2011). Effect of reverse transcriptase inhibitors on line-1 and ty1 reverse transcriptase activities and on line-1 retrotransposition. BMC Biochem., 12.","DOI":"10.1186\/1471-2091-12-18"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Jones, R.B., Garrison, K.E., Wong, J.C., Duan, E.H., Nixon, D.F., and Ostrowski, M.A. (2008). Nucleoside analogue reverse transcriptase inhibitors differentially inhibit human line-1 retrotransposition. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0001547"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.2174\/1568026619666190712204603","article-title":"Discovery and development of anti-hiv therapeutic agents: Progress towards improved hiv medication","volume":"19","author":"Maeda","year":"2019","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"296","DOI":"10.14218\/JCTH.2018.00016","article-title":"Hbv-hcv coinfection: Viral interactions, management, and viral reactivation","volume":"6","author":"Mavilia","year":"2018","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/S1473-3099(15)00485-5","article-title":"Prevalence and burden of hcv co-infection in people living with hiv: A global systematic review and meta-analysis","volume":"16","author":"Platt","year":"2016","journal-title":"Lancet Infect. Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1177\/0091270003258669","article-title":"Global burden of disease (gbd) for hepatitis c","volume":"44","year":"2004","journal-title":"J. Clin. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"45","DOI":"10.2147\/JHC.S221187","article-title":"Hepatocellular carcinoma mechanisms associated with chronic hcv infection and the impact of direct-acting antiviral treatment","volume":"7","author":"Dash","year":"2020","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1111\/liv.13659","article-title":"The impact of treatment of hepatitis c with daas on the occurrence of hcc","volume":"38","author":"Roche","year":"2018","journal-title":"Liver Int."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1053\/j.gastro.2017.03.018","article-title":"American gastroenterological association institute clinical practice update-expert review: Care of patients who have achieved a sustained virologic response after antiviral therapy for chronic hepatitis c infection","volume":"152","author":"Jacobson","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Eldafashi, N., Darlay, R., Shukla, R., McCain, M.V., Watson, R., Liu, Y.L., McStraw, N., Fathy, M., Fawzy, M.A., and Zaki, M.Y.W. (2021). A pdcd1 role in the genetic predisposition to nafld-hcc?. Cancers, 13.","DOI":"10.3390\/cancers13061412"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jhep.2014.02.030","article-title":"Carriage of the pnpla3 rs738409 c >g polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma","volume":"61","author":"Liu","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Tang, S., Zhang, J., Mei, T.T., Guo, H.Q., Wei, X.H., Zhang, W.Y., Liu, Y.L., Liang, S., Fan, Z.P., and Ma, L.X. (2019). Association of tm6sf2 rs58542926 t\/c gene polymorphism with hepatocellular carcinoma: A meta-analysis. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-6173-4"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.jhep.2020.11.024","article-title":"Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores","volume":"74","author":"Bianco","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Ponomaryova, A.A., Rykova, E.Y., Gervas, P.A., Cherdyntseva, N.V., Mamedov, I.Z., and Azhikina, T.L. (2020). Aberrant methylation of line-1 transposable elements: A search for cancer biomarkers. Cells, 9.","DOI":"10.3390\/cells9092017"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/s41598-018-36470-5","article-title":"Methylation of line-1 in cell-free DNA serves as a liquid biopsy biomarker for human breast cancers and dog mammary tumors","volume":"9","author":"Lee","year":"2019","journal-title":"Sci. Rep."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/20\/5079\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:11:33Z","timestamp":1760166693000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/20\/5079"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,11]]},"references-count":62,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["cancers13205079"],"URL":"https:\/\/doi.org\/10.3390\/cancers13205079","relation":{},"ISSN":["2072-6694"],"issn-type":[{"type":"electronic","value":"2072-6694"}],"subject":[],"published":{"date-parts":[[2021,10,11]]}}}