Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine

Torre, 2015, Global cancer statistics, 2012, CA Cancer J Clin, 65, 87, 10.3322/caac.21262 Bertuccio, 2017, Global trends and predictions in hepatocellular carcinoma mortality, J Hepatol, 67, 302, 10.1016/j.jhep.2017.03.011 Yang, 2017, Characteristics, management, and outcomes of patients with hepatocellular carcinoma in Africa: a multicountry observational study from the Africa Liver Cancer Consortium, Lancet Gastroenterol Hepatol, 2, 103, 10.1016/S2468-1253(16)30161-3 GBD, 2015, Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013, Lancet, 385, 117, 10.1016/S0140-6736(14)61682-2 Higashi, 2017, Hepatic stellate cells as key target in liver fibrosis, Adv Drug Deliv Rev, 10.1016/j.addr.2017.05.007 Mokdad, 2017, Trends and patterns of disparities in cancer mortality among us counties, 1980–2014, JAMA, 317, 388, 10.1001/jama.2016.20324 White, 2017, Incidence of hepatocellular carcinoma in all 50 United States, from 2000 through 2012, Gastroenterology, 152, 812, 10.1053/j.gastro.2016.11.020 Ryerson, 2016, Annual Report to the Nation on the Status of Cancer, 1975–2012, featuring the increasing incidence of liver cancer, Cancer, 122, 1312, 10.1002/cncr.29936 Petrick, 2016, Future of hepatocellular carcinoma incidence in the United States forecast through 2030, J Clin Oncol, 34, 1787, 10.1200/JCO.2015.64.7412 Nakagawa, 2016, Molecular liver cancer prevention in cirrhosis by organ transcriptome analysis and lysophosphatidic acid pathway inhibition, Cancer Cell, 30, 879, 10.1016/j.ccell.2016.11.004 Parikh, 2017, Cost effectiveness of regorafenib as second-line therapy for patients with advanced hepatocellular carcinoma, Cancer, 123, 3725, 10.1002/cncr.30863 2017, Comprehensive and integrative genomic characterization of hepatocellular carcinoma, Cell, 169, 1327, 10.1016/j.cell.2017.05.046 Goossens, 2015, Molecular classification of hepatocellular carcinoma: potential therapeutic implications, Hepat Oncol, 2, 371, 10.2217/hep.15.26 Hoshida, 2012, Prevention of hepatocellular carcinoma: potential targets, experimental models, and clinical challenges, Curr Cancer Drug Targets, 12, 1129 Bode, 2009, Cancer prevention research – then and now, Nat Rev Cancer, 9, 508, 10.1038/nrc2646 Bauman, 2016, Oral cancer chemoprevention-the end of EPOC, the beginning of an epoch of molecular selection, JAMA Oncol, 2, 178, 10.1001/jamaoncol.2015.4637 Le Magnen, 2016, Optimizing mouse models for precision cancer prevention, Nat Rev Cancer, 16, 187, 10.1038/nrc.2016.1 Maresso, 2015, Molecular cancer prevention: Current status and future directions, CA Cancer J Clin, 65, 345, 10.3322/caac.21287 Spira, 2017, Precancer atlas to drive precision prevention trials, Cancer Res, 77, 1510, 10.1158/0008-5472.CAN-16-2346 Bruix, 2011, Maintenance therapy with peginterferon alfa-2b does not prevent hepatocellular carcinoma in cirrhotic patients with chronic hepatitis C, Gastroenterology, 140, 1990, 10.1053/j.gastro.2011.03.010 Lok, 2011, Maintenance peginterferon therapy and other factors associated with hepatocellular carcinoma in patients with advanced hepatitis C, Gastroenterology, 140, 840, 10.1053/j.gastro.2010.11.050 1998, Effect of interferon-alpha on progression of cirrhosis to hepatocellular carcinoma: a retrospective cohort study. International Interferon-alpha Hepatocellular Carcinoma Study Group, Lancet, 351, 1535, 10.1016/S0140-6736(98)07236-5 Okita, 2015, Peretinoin after curative therapy of hepatitis C-related hepatocellular carcinoma: a randomized double-blind placebo-controlled study, J Gastroenterol, 50, 191, 10.1007/s00535-014-0956-9 Hoshida, 2014, Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma, J Hepatol, 61, S79, 10.1016/j.jhep.2014.07.010 Heimbach, 2017, Aasld guidelines for the treatment of hepatocellular carcinoma, Hepatology Meyskens, 2011, Regulatory approval of cancer risk-reducing (chemopreventive) drugs: moving what we have learned into the clinic, Cancer Prev Res (Phila), 4, 311, 10.1158/1940-6207.CAPR-09-0014 Singal, 2014, Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis, PLoS Med, 11, e1001624, 10.1371/journal.pmed.1001624 Mittal, 2016, Effectiveness of surveillance for hepatocellular carcinoma in clinical practice: A United States cohort, J Hepatol, 65, 1148, 10.1016/j.jhep.2016.07.025 Singal, 2017, Hepatocellular carcinoma screening associated with early tumor detection and improved survival among patients with cirrhosis in the US, Am J Med, 130, 1099, 10.1016/j.amjmed.2017.01.021 Cadier, 2017, Early detection and curative treatment of hepatocellular carcinoma: A cost-effectiveness analysis in France and in the United States, Hepatology, 65, 1237, 10.1002/hep.28961 Mourad, 2014, Hepatocellular carcinoma screening in patients with compensated hepatitis C virus (HCV)-related cirrhosis aware of their HCV status improves survival: a modeling approach, Hepatology, 59, 1471, 10.1002/hep.26944 Singal, 2015, Hepatocellular carcinoma from epidemiology to prevention: translating knowledge into practice, Clin Gastroenterol Hepatol, 13, 2140, 10.1016/j.cgh.2015.08.014 Singal, 2017, Mailed outreach program increases ultrasound screening of patients with cirrhosis for hepatocellular carcinoma, Gastroenterology, 152, 608, 10.1053/j.gastro.2016.10.042 Goossens, 2017, Tailored algorithms for hepatocellular carcinoma surveillance: Is one-size-fits-all strategy outdated?, Curr Hepatol Rep, 16, 64, 10.1007/s11901-017-0336-z Atiq, 2017, An assessment of benefits and harms of hepatocellular carcinoma surveillance in patients with cirrhosis, Hepatology, 65, 1196, 10.1002/hep.28895 Germani, 2011, Assessment of fibrosis and cirrhosis in liver biopsies: an update, Semin Liver Dis, 31, 82, 10.1055/s-0031-1272836 Tsochatzis, 2014, Collagen proportionate area is superior to other histological methods for sub-classifying cirrhosis and determining prognosis, J Hepatol, 60, 948, 10.1016/j.jhep.2013.12.023 Huang, 2014, Image analysis of liver biopsy samples measures fibrosis and predicts clinical outcome, J Hepatol, 61, 22, 10.1016/j.jhep.2014.02.031 Wang, 2015, Automated biphasic morphological assessment of hepatitis B-related liver fibrosis using second harmonic generation microscopy, Sci Rep, 5, 12962, 10.1038/srep12962 Suk, 2017, Prognostic significance of hemodynamic and clinical stages in the prediction of hepatocellular carcinoma, J Clin Gastroenterol, 51, 285, 10.1097/MCG.0000000000000671 Motosugi, 2013, Liver stiffness measured by magnetic resonance elastography as a risk factor for hepatocellular carcinoma: a preliminary case-control study, Eur Radiol, 23, 156, 10.1007/s00330-012-2571-6 Singh, 2013, Liver stiffness is associated with risk of decompensation, liver cancer, and death in patients with chronic liver diseases: a systematic review and meta-analysis, Clin Gastroenterol Hepatol, 11, 1573, 10.1016/j.cgh.2013.07.034 Shin, 2015, Liver stiffness-based model for prediction of hepatocellular carcinoma in chronic hepatitis B virus infection: comparison with histological fibrosis, Liver Int, 35, 1054, 10.1111/liv.12621 Wang, 2016, Liver stiffness-based score in hepatoma risk assessment for chronic hepatitis C patients after successful antiviral therapy, Liver Int, 36, 1793, 10.1111/liv.13179 Lee, 2009, Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer, Int J Epidemiol, 38, 1497, 10.1093/ije/dyp280 Makarova-Rusher, 2016, Population attributable fractions of risk factors for hepatocellular carcinoma in the United States, Cancer, 122, 1757, 10.1002/cncr.29971 Niu, 2016, The epidemiological investigation on the risk factors of hepatocellular carcinoma: a case-control study in Southeast China, Medicine, 95, e2758, 10.1097/MD.0000000000002758 Yu, 2017, Influence of metabolic risk factors on risk of hepatocellular carcinoma and liver-related death in men with chronic hepatitis B: a large cohort study, Gastroenterology, 153, 1006, 10.1053/j.gastro.2017.07.001 Zhong, 2012, Epidermal growth factor gene polymorphism and risk of hepatocellular carcinoma: a meta-analysis, PLoS One, 7, e32159, 10.1371/journal.pone.0032159 Nahon, 2012, A variant in myeloperoxidase promoter hastens the emergence of hepatocellular carcinoma in patients with HCV-related cirrhosis, J Hepatol, 56, 426, 10.1016/j.jhep.2011.08.010 Zhang, 2010, Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers, Nat Genet, 42, 755, 10.1038/ng.638 Jiang, 2013, Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma, Nat Genet, 45, 72, 10.1038/ng.2483 Kumar, 2011, Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma, Nat Genet, 43, 455, 10.1038/ng.809 Miki, 2011, Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers, Nat Genet, 43, 797, 10.1038/ng.876 Huang, 2017, Diversity of the association of serum levels and genetic variants of MHC class I polypeptide-related chain A with liver fibrosis in chronic hepatitis C, Oncotarget, 8, 32618, 10.18632/oncotarget.15941 Zhang, 2017, Genetic polymorphism of epidermal growth factor rs4444903 influences susceptibility to HCV-related liver cirrhosis and hepatocellular carcinoma in a Chinese Han population, Clin Lab, 63, 845, 10.7754/Clin.Lab.2016.161203 Trepo, 2016, PNPLA3 gene in liver diseases, J Hepatol, 65, 399, 10.1016/j.jhep.2016.03.011 Donati, 2017, Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease, Cancer Med, 6, 1930, 10.1002/cam4.1078 Donati, 2017, MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals, Sci Rep, 7, 4492, 10.1038/s41598-017-04991-0 Matsuura, 2017, Genome-wide association study identifies TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus infection, Gastroenterology, 152, 1383, 10.1053/j.gastro.2017.01.041 Besheer, 2017, Prediction of fibrosis progression rate in patients with chronic hepatitis C genotype 4: role of cirrhosis risk score and host factors, J Interferon Cytokine Res, 37, 97, 10.1089/jir.2016.0111 Duarte-Salles, 2016, Circulating osteopontin and prediction of hepatocellular carcinoma development in a large European population, Cancer Prev Res (Phila), 9, 758, 10.1158/1940-6207.CAPR-15-0434 Mazziotti, 2002, Serum insulin-like growth factor I evaluation as a useful tool for predicting the risk of developing hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis: a prospective study, Cancer, 95, 2539, 10.1002/cncr.11002 Verhelst, 2017, A glycomics-based test predicts the development of hepatocellular carcinoma in cirrhosis, Clin Cancer Res, 23, 2750, 10.1158/1078-0432.CCR-16-1500 Pepe, 2008, Pivotal evaluation of the accuracy of a biomarker used for classification or prediction: standards for study design, J Natl Cancer Inst, 100, 1432, 10.1093/jnci/djn326 Goossens, 2015, Cancer biomarker discovery and validation, Transl Cancer Res, 4, 256 Singal, 2009, Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis, Aliment Pharmacol Ther, 30, 37, 10.1111/j.1365-2036.2009.04014.x Singal, 2012, Effectiveness of hepatocellular carcinoma surveillance in patients with cirrhosis, Cancer Epidemiol Biomarkers Prev, 21, 793, 10.1158/1055-9965.EPI-11-1005 Del Poggio, 2014, Factors that affect efficacy of ultrasound surveillance for early stage hepatocellular carcinoma in patients with cirrhosis, Clin Gastroenterol Hepatol, 12, 1927, 10.1016/j.cgh.2014.02.025 Simmons, 2017, Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis, Aliment Pharmacol Ther, 45, 169, 10.1111/apt.13841 Song, 2016, Controversies regarding and perspectives on clinical utility of biomarkers in hepatocellular carcinoma, World J Gastroenterol, 22, 262, 10.3748/wjg.v22.i1.262 Wang, 2016, The doylestown algorithm: a test to improve the performance of AFP in the detection of hepatocellular carcinoma, Cancer Prev Res (Phila), 9, 172, 10.1158/1940-6207.CAPR-15-0186 Johnson, 2014, The detection of hepatocellular carcinoma using a prospectively developed and validated model based on serological biomarkers, Cancer Epidemiol Biomarkers Prev, 23, 144, 10.1158/1055-9965.EPI-13-0870 Yang, 2017, Improved performance of serum alpha-fetoprotein for hepatocellular carcinoma diagnosis in HCV cirrhosis with normal alanine transaminase, Cancer Epidemiol Biomarkers Prev, 26, 1085, 10.1158/1055-9965.EPI-16-0747 Yu, 2011, CT and MRI improve detection of hepatocellular carcinoma, compared with ultrasound alone, in patients with cirrhosis, Clin Gastroenterol Hepatol, 9, 161, 10.1016/j.cgh.2010.09.017 Pocha, 2013, Surveillance for hepatocellular cancer with ultrasonography vs. computed tomography–a randomised study, Aliment Pharmacol Ther, 38, 303, 10.1111/apt.12370 Kim, 2017, MRI with liver-specific contrast for surveillance of patients with cirrhosis at high risk of hepatocellular carcinoma, JAMA Oncol, 3, 456, 10.1001/jamaoncol.2016.3147 Besa, 2016, Hepatocellular carcinoma detection: diagnostic performance of a simulated abbreviated MRI protocol combining diffusion-weighted and T1-weighted imaging at the delayed phase post gadoxetic acid, Abdom Radiol, 1 Furlan, 2012, Hepatocellular carcinoma presenting at contrast-enhanced multi–detector-row computed tomography or gadolinium-enhanced magnetic resonance imaging as a small (≤2 cm), indeterminate nodule: growth rate and optimal interval time for imaging follow-up, J Comput Assist Tomogr, 36, 20, 10.1097/RCT.0b013e31823ed462 Taouli, 2005, Growth rate of hepatocellular carcinoma: evaluation with serial computed tomography or magnetic resonance imaging, J Comput Assist Tomogr, 29, 425, 10.1097/01.rct.0000164036.85327.05 Santi, 2010, Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival, J Hepatol, 53, 291, 10.1016/j.jhep.2010.03.010 Trinchet, 2011, Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities, Hepatology, 54, 1987, 10.1002/hep.24545 Levin, 2008, Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology∗†, CA: A Cancer J Clin, 58, 130 Tice, 2008, Using clinical factors and mammographic breast density to estimate breast cancer risk: development and validation of a new predictive model, Ann Intern Med, 148, 337, 10.7326/0003-4819-148-5-200803040-00004 Bolutayo, 2017, Reducing liver cancer risk in african-born immigrants through culturally targeted hepatitis b group education programs, J Cancer Educ Goossens, 2017, Cost-effectiveness of risk score-stratified hepatocellular carcinoma screening in patients with cirrhosis, Clin Transl Gastroenterol, 8, e101, 10.1038/ctg.2017.26 Petrick, 2016, International trends in liver cancer incidence, overall and by histologic subtype, 1978–2007, Int J Cancer, 139, 1534, 10.1002/ijc.30211 Chu, 2017, Aflatoxin B1 exposure increases the risk of cirrhosis and hepatocellular carcinoma in chronic hepatitis B virus carriers, Int J Cancer, 141, 711, 10.1002/ijc.30782 Zheng, 2017, Serum microcystin levels positively linked with risk of hepatocellular carcinoma: A case-control study in southwest China, Hepatology, 66, 1519, 10.1002/hep.29310 Abbas, 2015, Hepatitis D and hepatocellular carcinoma, World journal of hepatology, 7, 777, 10.4254/wjh.v7.i5.777 Levrero, 2016, Mechanisms of HBV-induced hepatocellular carcinoma, J Hepatol, 64, S84, 10.1016/j.jhep.2016.02.021 Chen, 2006, Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level, JAMA, 295, 65, 10.1001/jama.295.1.65 Yang, 2008, Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma, J Natl Cancer Inst, 100, 1134, 10.1093/jnci/djn243 Livingston, 2007, Hepatitis B virus genotypes in Alaska Native people with hepatocellular carcinoma: preponderance of genotype F, J Infect Dis, 195, 5, 10.1086/509894 Ni, 2012, Minimization of hepatitis B infection by a 25-year universal vaccination program, J Hepatol, 57, 730, 10.1016/j.jhep.2012.05.021 Chang, 2009, Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study, J Natl Cancer Inst, 101, 1348, 10.1093/jnci/djp288 Yang, 2009, Interferon therapy in chronic hepatitis B reduces progression to cirrhosis and hepatocellular carcinoma: a meta-analysis, J Viral Hepat, 16, 265, 10.1111/j.1365-2893.2009.01070.x Liaw, 2004, Lamivudine for patients with chronic hepatitis B and advanced liver disease, N Engl J Med, 351, 1521, 10.1056/NEJMoa033364 Yuen, 2007, Long-term lamivudine therapy reduces the risk of long-term complications of chronic hepatitis B infection even in patients without advanced disease, Antivir Ther, 12, 1295, 10.1177/135965350701200816 Matsumoto, 2005, Efficacy of lamivudine for preventing hepatocellular carcinoma in chronic hepatitis B: A multicenter retrospective study of 2795 patients, Hepatol Res, 32, 173, 10.1016/j.hepres.2005.02.006 Papatheodoridis, 2015, Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy, J Hepatol, 62, 956, 10.1016/j.jhep.2015.01.002 Su, 2016, Four-year entecavir therapy reduces hepatocellular carcinoma, cirrhotic events and mortality in chronic hepatitis B patients, Liver Int, 36, 1755, 10.1111/liv.13253 Kim, 2015, Impact of long-term tenofovir disoproxil fumarate on incidence of hepatocellular carcinoma in patients with chronic hepatitis B, Cancer, 121, 3631, 10.1002/cncr.29537 Liang, 2016, Peginterferon is superior to nucleos(t)ide analogues for prevention of hepatocellular carcinoma in chronic hepatitis B, J Infect Dis, 213, 966, 10.1093/infdis/jiv547 Sun, 2014, Nucleot(s)ide analogues for hepatitis B virus-related hepatocellular carcinoma after curative treatment: a systematic review and meta-analysis, PLoS One, 9, e102761, 10.1371/journal.pone.0102761 Huang, 2015, Antiviral therapy improves postoperative survival in patients with hepatocellular carcinoma: a randomized controlled trial, Ann Surg, 261, 56, 10.1097/SLA.0000000000000858 Cho, 2014, Patients with chronic hepatitis B treated with oral antiviral therapy retain a higher risk for HCC compared with patients with inactive stage disease, Gut, 63, 1943, 10.1136/gutjnl-2013-306409 Kim, 2017, Low-level viremia and the increased risk of hepatocellular carcinoma in patients receiving entecavir treatment, Hepatology, 66, 335, 10.1002/hep.28916 Polaris Observatory, 2017, Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study, Lancet Gastroenterol Hepatol, 2, 161, 10.1016/S2468-1253(16)30181-9 Torres, 2017, The oncologic burden of hepatitis C virus infection: A clinical perspective, CA Cancer J Clin, 67, 411, 10.3322/caac.21403 Baumert, 2017, Hepatitis C-related hepatocellular carcinoma in the era of new generation antivirals, BMC Med, 15, 52, 10.1186/s12916-017-0815-7 Waziry, 2016, Trends in hepatocellular carcinoma among people with HBV or HCV notification in Australia (2000–2014), J Hepatol, 65, 1086, 10.1016/j.jhep.2016.08.010 Sievert, 2014, Enhanced antiviral treatment efficacy and uptake in preventing the rising burden of hepatitis C-related liver disease and costs in Australia, J Gastroenterol Hepatol, 29, 1, 10.1111/jgh.12677 Harris, 2014, Increased uptake and new therapies are needed to avert rising hepatitis C-related end stage liver disease in England: Modelling the predicted impact of treatment under different scenarios, J Hepatol, 61, 530, 10.1016/j.jhep.2014.05.008 Nasrullah, 2017, HCV elimination – lessons learned from a small Eurasian country. Georgia, Nat Rev Gastroenterol Hepatol, 14, 447, 10.1038/nrgastro.2017.100 Stasi, 2016, The epidemiological changes of HCV and HBV infections in the era of new antiviral therapies and the anti-HBV vaccine, J Infect Public Health, 9, 389, 10.1016/j.jiph.2015.05.004 Chhatwal, 2016, Hepatitis C Disease Burden in the United States in the era of oral direct-acting antivirals, Hepatology, 64, 1442, 10.1002/hep.28571 Fauvelle, 2016, Hepatitis C virus vaccine candidates inducing protective neutralizing antibodies, Expert Rev Vaccines, 1 Billerbeck, 2017, Mouse models of acute and chronic hepacivirus infection, Science, 357, 204, 10.1126/science.aal1962 Bandiera, 2016, Chronic hepatitis C virus infection and pathogenesis of hepatocellular carcinoma, Curr Opin Virol, 20, 99, 10.1016/j.coviro.2016.09.010 Samur, 2017, Cost-effectiveness of pre versus post liver transplant hepatitis C treatment with direct-acting antivirals, Clin Gastroenterol Hepatol Asselah, 2014, Is screening baby boomers for HCV enough? A call to screen for hepatitis C virus in persons from countries of high endemicity, Liver Int, 34, 1447, 10.1111/liv.12599 Cheung, 2016, Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis, J Hepatol, 65, 741, 10.1016/j.jhep.2016.06.019 Nahon, 2017, Eradication of hepatitis C virus infection in patients with cirrhosis reduces risk of liver and non-liver complications, Gastroenterology, 152, 142, 10.1053/j.gastro.2016.09.009 Kanwal, 2017, Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents, Gastroenterology, 153, 996, 10.1053/j.gastro.2017.06.012 Ono, 2017, Persisting risk of hepatocellular carcinoma after hepatitis C virus cure monitored by a liver transcriptome signature, Hepatology, 66, 1344, 10.1002/hep.29203 Aydin, 2017, Interferon-alpha-induced hepatitis C virus clearance restores p53 tumor suppressor more than direct-acting antivirals, Hepatol Commun, 10.1002/hep4.1025 La Vecchia, 2014, Trends in alcohol consumption in Europe and their impact on major alcohol-related cancers, Eur J Cancer Prev, 23, 319, 10.1097/CEJ.0b013e32836562f1 Turati, 2014, Alcohol and liver cancer: a systematic review and meta-analysis of prospective studies, Ann Oncol, 25, 1526, 10.1093/annonc/mdu020 Stickel, 2015, Alcoholic cirrhosis and hepatocellular carcinoma, Adv Exp Med Biol, 815, 113, 10.1007/978-3-319-09614-8_7 Yuan, 2004, Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the U.S., Cancer, 101, 1009, 10.1002/cncr.20427 Vandenbulcke, 2016, Alcohol intake increases the risk of HCC in hepatitis C virus-related compensated cirrhosis: A prospective study, J Hepatol, 65, 543, 10.1016/j.jhep.2016.04.031 Totoki, 2014, Trans-ancestry mutational landscape of hepatocellular carcinoma genomes, Nat Genet, 46, 1267, 10.1038/ng.3126 Heckley, 2011, U GG. How the risk of liver cancer changes after alcohol cessation: a review and meta-analysis of the current literature, BMC Cancer, 11, 446, 10.1186/1471-2407-11-446 Day, 2007, Treatment of alcoholic liver disease, Liver Transpl, 13, S69, 10.1002/lt.21336 La Vecchia, 2007, Alcohol and liver cancer, Eur J Cancer Prev, 16, 495, 10.1097/CEJ.0b013e3280145b5d Younossi, 2016, Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes, Hepatology, 64, 73, 10.1002/hep.28431 Bhaskaran, 2014, Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5.24 million UK adults, Lancet, 384, 755, 10.1016/S0140-6736(14)60892-8 El-Serag, 2006, The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence, Clin Gastroenterol Hepatol, 4, 369, 10.1016/j.cgh.2005.12.007 Wang, 2012, Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies, Int J Cancer, 130, 1639, 10.1002/ijc.26165 Mittal, 2016, Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease, Clin Gastroenterol Hepatol, 14, 124, 10.1016/j.cgh.2015.07.019 Neuschwander-Tetri, 2017, Non-alcoholic fatty liver disease, BMC Med, 15, 45, 10.1186/s12916-017-0806-8 Park, 2010, Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression, Cell, 140, 197, 10.1016/j.cell.2009.12.052 Tilg, 2006, Nonalcoholic fatty liver disease: Cytokine-adipokine interplay and regulation of insulin resistance, Gastroenterology, 131, 934, 10.1053/j.gastro.2006.05.054 Nakagawa, 2014, ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development, Cancer Cell, 26, 331, 10.1016/j.ccr.2014.07.001 Yoshimoto, 2013, Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome, Nature, 499, 97, 10.1038/nature12347 Kettner, 2016, Circadian homeostasis of liver metabolism suppresses hepatocarcinogenesis, Cancer Cell, 30, 909, 10.1016/j.ccell.2016.10.007 Ma, 2016, NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis, Nature, 531, 253, 10.1038/nature16969 Gomes, 2016, Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma, Cancer Cell, 30, 161, 10.1016/j.ccell.2016.05.020 Loo, 2017, Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity, Cancer Discov, 7, 522, 10.1158/2159-8290.CD-16-0932 Giles, 2017, Thermoneutral housing exacerbates nonalcoholic fatty liver disease in mice and allows for sex-independent disease modeling, Nat Med, 23, 829, 10.1038/nm.4346 Asgharpour, 2016, A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer, J Hepatol, 65, 579, 10.1016/j.jhep.2016.05.005 Teufel, 2016, Comparison of gene expression patterns between mouse models of nonalcoholic fatty liver disease and liver tissues from patients, Gastroenterology, 151, 513, 10.1053/j.gastro.2016.05.051 Yang, 2014, Increased intake of vegetables, but not fruit, reduces risk for hepatocellular carcinoma: a meta-analysis, Gastroenterology, 147, 1031, 10.1053/j.gastro.2014.08.005 Wen, 2012, Hepatocellular carcinoma risk prediction model for the general population: the predictive power of transaminases, J Natl Cancer Inst, 104, 1599, 10.1093/jnci/djs372 Cao, 2011, MYC phosphorylation, activation, and tumorigenic potential in hepatocellular carcinoma are regulated by HMG-CoA reductase, Cancer Res, 71, 2286, 10.1158/0008-5472.CAN-10-3367 Roudier, 2006, Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs, Mol Cancer Ther, 5, 2706, 10.1158/1535-7163.MCT-06-0352 Ghalali, 2017, Atorvastatin decreases HBx-induced phospho-Akt in hepatocytes via P2X receptors, Mol Cancer Res, 15, 714, 10.1158/1541-7786.MCR-16-0373 Relja, 2011, Simvastatin modulates the adhesion and growth of hepatocellular carcinoma cells via decrease of integrin expression and ROCK, Int J Oncol, 38, 879, 10.3892/ijo.2010.892 Wang, 2006, Anti-inflammatory effect of pitavastatin on NF-kappaB activated by TNF-alpha in hepatocellular carcinoma cells, Biol Pharm Bull, 29, 634, 10.1248/bpb.29.634 Higashi, 2016, Statin attenuates cell proliferative ability via TAZ (WWTR1) in hepatocellular carcinoma, Med Oncol, 33, 123, 10.1007/s12032-016-0845-6 Yang, 2010, Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies, Cancer Res, 70, 7699, 10.1158/0008-5472.CAN-10-1626 Sutter, 2005, Cell cycle arrest and apoptosis induction in hepatocellular carcinoma cells by HMG-CoA reductase inhibitors. Synergistic antiproliferative action with ligands of the peripheral benzodiazepine receptor, J Hepatol, 43, 808, 10.1016/j.jhep.2005.04.010 Kah, 2012, Selective induction of apoptosis by HMG-CoA reductase inhibitors in hepatoma cells and dependence on p53 expression, Oncol Rep, 28, 1077, 10.3892/or.2012.1860 Wang, 2013, Simvastatin ameliorates liver fibrosis via mediating nitric oxide synthase in rats with non-alcoholic steatohepatitis-related liver fibrosis, PLoS One, 8, e76538, 10.1371/journal.pone.0076538 Chong, 2015, Fluvastatin attenuates hepatic steatosis-induced fibrogenesis in rats through inhibiting paracrine effect of hepatocyte on hepatic stellate cells, BMC Gastroenterol, 15, 22, 10.1186/s12876-015-0248-8 Marrone, 2013, The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial-stellate cell deactivation induced by statins, J Hepatol, 58, 98, 10.1016/j.jhep.2012.08.026 Marinho, 2017, Rosuvastatin limits the activation of hepatic stellate cells in diet-induced obese mice, Hepatol Res, 47, 928, 10.1111/hepr.12821 Uschner, 2015, Statins activate the canonical hedgehog-signaling and aggravate non-cirrhotic portal hypertension, but inhibit the non-canonical hedgehog signaling and cirrhotic portal hypertension, Sci Rep, 5, 14573, 10.1038/srep14573 Kim, 2017, Effect of statin on hepatocellular carcinoma in patients with type 2 diabetes: A nationwide nested case-control study, Int J Cancer, 140, 798, 10.1002/ijc.30506 Tsan, 2012, Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection, J Clin Oncol, 30, 623, 10.1200/JCO.2011.36.0917 Tsan, 2013, Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection, J Clin Oncol, 31, 1514, 10.1200/JCO.2012.44.6831 Simon, 2016, Atorvastatin and fluvastatin are associated with dose-dependent reductions in cirrhosis and hepatocellular carcinoma, among patients with hepatitis C virus: Results from ERCHIVES, Hepatology, 64, 47, 10.1002/hep.28506 Simon, 2015, Statin use is associated with a reduced risk of fibrosis progression in chronic hepatitis C, J Hepatol, 62, 18, 10.1016/j.jhep.2014.08.013 Chang, 2017, Statins decrease the risk of decompensation in hepatitis B virus- and hepatitis C virus-related cirrhosis: A population-based study, Hepatology, 66, 896, 10.1002/hep.29172 Lee, 2017, The occurrence of hepatocellular carcinoma in different risk stratifications of clinically non-cirrhotic non-alcoholic fatty liver disease, Int J Cancer, 10.1002/ijc.30784 Singh, 2013, Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis, Gastroenterology, 144, 323, 10.1053/j.gastro.2012.10.005 Cholesterol Treatment Trialists, 2012, Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy, PLoS One, 7, e29849, 10.1371/journal.pone.0029849 Zhou, 2016, Systematic review with network meta-analysis: statins and risk of hepatocellular carcinoma, Oncotarget, 7, 21753, 10.18632/oncotarget.7832 Zheng, 2013, Prognostic significance of AMPK activation and therapeutic effects of metformin in hepatocellular carcinoma, Clin Cancer Res, 19, 5372, 10.1158/1078-0432.CCR-13-0203 Zhou, 2016, Metformin suppresses hypoxia-induced stabilization of HIF-1alpha through reprogramming of oxygen metabolism in hepatocellular carcinoma, Oncotarget, 7, 873, 10.18632/oncotarget.6418 Chen, 2013, Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies, Gut, 62, 606, 10.1136/gutjnl-2011-301708 Buzzai, 2007, Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth, Cancer Res, 67, 6745, 10.1158/0008-5472.CAN-06-4447 Tsai, 2017, Metformin promotes apoptosis in hepatocellular carcinoma through the CEBPD-induced autophagy pathway, Oncotarget, 8, 13832, 10.18632/oncotarget.14640 DePeralta, 2016, Metformin prevents hepatocellular carcinoma development by suppressing hepatic progenitor cell activation in a rat model of cirrhosis, Cancer, 122, 1216, 10.1002/cncr.29912 Ma, 2017, Meta-analysis of studies using metformin as a reducer for liver cancer risk in diabetic patients, Medicine, 96, e6888, 10.1097/MD.0000000000006888 Thomou, 2017, Adipose-derived circulating miRNAs regulate gene expression in other tissues, Nature, 542, 450, 10.1038/nature21365 Soberg, 2017, FGF21 is a sugar-induced hormone associated with sweet intake and preference in humans, Cell Metab, 25, 1045, 10.1016/j.cmet.2017.04.009 von Holstein-Rathlou, 2016, FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver, Cell Metab, 23, 335, 10.1016/j.cmet.2015.12.003 Liu, 2016, Lack of fibroblast growth factor 21 accelerates metabolic liver injury characterized by steatohepatities in mice, Am J Cancer Res, 6, 1011 Gong, 2016, Fibroblast growth factor 21 improves hepatic insulin sensitivity by inhibiting mammalian target of rapamycin complex 1 in mice, Hepatology, 64, 425, 10.1002/hep.28523 Lee, 2016, An engineered FGF21 variant, LY2405319, can prevent non-alcoholic steatohepatitis by enhancing hepatic mitochondrial function, Am J Transl Res, 8, 4750 Hou, 2014, Hepatic RIG-I predicts survival and interferon-alpha therapeutic response in hepatocellular carcinoma, Cancer Cell, 25, 49, 10.1016/j.ccr.2013.11.011 Singh, 2014, Chemopreventive strategies in hepatocellular carcinoma, Nat Rev Gastroenterol Hepatol, 11, 45, 10.1038/nrgastro.2013.143 Petrick, 2015, NSAID use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the liver cancer pooling project, Cancer Prev Res (Phila), 8, 1156, 10.1158/1940-6207.CAPR-15-0126 Dapito, 2012, Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4, Cancer Cell, 21, 504, 10.1016/j.ccr.2012.02.007 Hu, 2003, Cyclooxygenase 2 (COX2)-prostanoid pathway and liver diseases, Prostaglandins Leukot Essent Fatty Acids, 69, 329, 10.1016/j.plefa.2003.07.001 Chen, 2017, Hepatic cyclooxygenase-2 overexpression induced spontaneous hepatocellular carcinoma formation in mice, Oncogene, 36, 4415, 10.1038/onc.2017.73 Xiong, 2017, LncRNA HULC promotes the growth of hepatocellular carcinoma cells via stabilizing COX-2 protein, Biochem Biophys Res Commun, 490, 693, 10.1016/j.bbrc.2017.06.103 Xu, 2016, Activated hepatic stellate cells promote liver cancer by induction of myeloid-derived suppressor cells through cyclooxygenase-2, Oncotarget, 7, 8866, 10.18632/oncotarget.6839 Lee, 2014, Synergistic effect of simvastatin plus NS398 on inhibition of proliferation and survival in hepatocellular carcinoma cell line, J Gastroenterol Hepatol, 29, 1299, 10.1111/jgh.12503 Takami, 2016, A randomised controlled trial of meloxicam, a Cox-2 inhibitor, to prevent hepatocellular carcinoma recurrence after initial curative treatment, Hepatol Int, 10, 799, 10.1007/s12072-016-9704-y Lee, 2015, Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma, Gastroenterology, 148, 1383, 10.1053/j.gastro.2015.02.055 Qiu, 2015, A multicenter, randomized, observation-controlled clinical trial to evaluate the efficacy and safety of thymalfasin adjuvant therapy in patients with HBV-related HCC after curative resection – first announcement of the protocol, Expert Opin Biol Ther, 15, S133, 10.1517/14712598.2015.1039979 Friedman, 2017, A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis, Hepatology Ratziu, 2016, Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening, Gastroenterology, 150, 1147, 10.1053/j.gastro.2016.01.038 Duarte-Salles, 2015, Dietary fat, fat subtypes and hepatocellular carcinoma in a large European cohort, Int J Cancer, 137, 2715, 10.1002/ijc.29643 Sawada, 2012, Consumption of n-3 fatty acids and fish reduces risk of hepatocellular carcinoma, Gastroenterology, 142, 1468, 10.1053/j.gastro.2012.02.018 Lim, 2009, Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through blocking beta-catenin and cyclooxygenase-2, Mol Cancer Ther, 8, 3046, 10.1158/1535-7163.MCT-09-0551 Weylandt, 2011, Suppressed liver tumorigenesis in fat-1 mice with elevated omega-3 fatty acids is associated with increased omega-3 derived lipid mediators and reduced TNF-alpha, Carcinogenesis, 32, 897, 10.1093/carcin/bgr049 Freedman, 2010, Association of meat and fat intake with liver disease and hepatocellular carcinoma in the NIH-AARP cohort, J Natl Cancer Inst, 102, 1354, 10.1093/jnci/djq301 Fedirko, 2014, Prediagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: a nested case-control study, Hepatology, 60, 1222, 10.1002/hep.27079 Wong, 2015, Adverse effects of vitamin D deficiency on outcomes of patients with chronic hepatitis B, Clin Gastroenterol Hepatol, 13, 783, 10.1016/j.cgh.2014.09.050 Kwon, 2010, Vitamin D3 upregulated protein 1 suppresses TNF-alpha-induced NF-kappaB activation in hepatocarcinogenesis, J Immunol, 185, 3980, 10.4049/jimmunol.1000990 Li, 2012, Dysregulated Kruppel-like factor 4 and vitamin D receptor signaling contribute to progression of hepatocellular carcinoma, Gastroenterology, 143, 799, 10.1053/j.gastro.2012.05.043 Duran, 2016, P62/SQSTM1 by binding to vitamin D receptor inhibits hepatic stellate cell activity, fibrosis, and liver cancer, Cancer Cell, 30, 595, 10.1016/j.ccell.2016.09.004 Preziosi, 2017, Mice lacking liver-specific beta-catenin develop steatohepatitis and fibrosis after iron overload, J Hepatol, 67, 360, 10.1016/j.jhep.2017.03.012 Kato, 2007, Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C, J Gastroenterol, 42, 830, 10.1007/s00535-007-2095-z Saeki, 2016, Effects of an oral iron chelator, deferasirox, on advanced hepatocellular carcinoma, World J Gastroenterol, 22, 8967, 10.3748/wjg.v22.i40.8967 Cha, 2013, Branched-chain amino acids ameliorate fibrosis and suppress tumor growth in a rat model of hepatocellular carcinoma with liver cirrhosis, PLoS One, 8, e77899, 10.1371/journal.pone.0077899 Nakano, 2013, Branched-chain amino acids enhance premature senescence through mammalian target of rapamycin complex I-mediated upregulation of p21 protein, PLoS One, 8, e80411, 10.1371/journal.pone.0080411 Korenaga, 2015, Branched-chain amino acids reduce hepatic iron accumulation and oxidative stress in hepatitis C virus polyprotein-expressing mice, Liver Int, 35, 1303, 10.1111/liv.12675 Takegoshi, 2017, Branched-chain amino acids prevent hepatic fibrosis and development of hepatocellular carcinoma in a non-alcoholic steatohepatitis mouse model, Oncotarget, 8, 18191, 10.18632/oncotarget.15304 Terakura, 2012, Preventive effects of branched-chain amino acid supplementation on the spontaneous development of hepatic preneoplastic lesions in C57BL/KsJ-db/db obese mice, Carcinogenesis, 33, 2499, 10.1093/carcin/bgs303 Kawaguchi, 2014, Branched-chain amino acids prevent hepatocarcinogenesis and prolong survival of patients with cirrhosis, Clin Gastroenterol Hepatol, 12, 1012, 10.1016/j.cgh.2013.08.050 Kennedy, 2017, Coffee, including caffeinated and decaffeinated coffee, and the risk of hepatocellular carcinoma: a systematic review and dose-response meta-analysis, BMJ Open, 7, e013739, 10.1136/bmjopen-2016-013739 Aleksandrova, 2015, The association of coffee intake with liver cancer risk is mediated by biomarkers of inflammation and hepatocellular injury: data from the European Prospective Investigation into Cancer and Nutrition, Am J Clin Nutr, 102, 1498, 10.3945/ajcn.115.116095 Xiao, 2014, Inverse associations of total and decaffeinated coffee with liver enzyme levels in National Health and Nutrition Examination Survey 1999–2010, Hepatology, 60, 2091, 10.1002/hep.27367 Bamia, 2015, Coffee, tea and decaffeinated coffee in relation to hepatocellular carcinoma in a European population: multicentre, prospective cohort study, Int J Cancer, 136, 1899, 10.1002/ijc.29214 Edling, 2014, Caffeine and the analog CGS 15943 inhibit cancer cell growth by targeting the phosphoinositide 3-kinase/Akt pathway, Cancer Biol Ther, 15, 524, 10.4161/cbt.28018 Nelson, 2017, The essential medicinal chemistry of curcumin, J Med Chem, 60, 1620, 10.1021/acs.jmedchem.6b00975 Veldt, 2006, Long-term clinical outcome and effect of glycyrrhizin in 1093 chronic hepatitis C patients with non-response or relapse to interferon, Scand J Gastroenterol, 41, 1087, 10.1080/00365520600641365 Morgan, 2015, A phase II randomized, controlled trial of S-adenosylmethionine in reducing serum alpha-fetoprotein in patients with hepatitis C cirrhosis and elevated AFP, Cancer Prev Res (Phila), 8, 864, 10.1158/1940-6207.CAPR-15-0029 Duvoux, 2015, MTOR inhibitor therapy: Does it prevent HCC recurrence after liver transplantation?, Transplant Rev (Orlando), 29, 168, 10.1016/j.trre.2015.02.003 Massoud, 2012, The use of sirolimus should be restricted in liver transplantation, J Hepatol, 56, 288, 10.1016/j.jhep.2011.06.012 Umemura, 2014, Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition, Cell Metab, 20, 133, 10.1016/j.cmet.2014.05.001 Burra, 2015, Neoplastic disease after liver transplantation: Focus on de novo neoplasms, World J Gastroenterol, 21, 8753, 10.3748/wjg.v21.i29.8753 Geissler, 2016, Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open-label phase 3 trial, Transplantation, 100, 116, 10.1097/TP.0000000000000965 Binder, 2015, Lysophosphatidic acid and sphingosine-1-phosphate: a concise review of biological function and applications for tissue engineering, Tissue Eng Part B Rev, 21, 531, 10.1089/ten.teb.2015.0107 Erstad, 2017, The autotaxin-lysophosphatidic acid pathway emerges as a therapeutic target to prevent liver cancer, Mol Cell Oncol, 4, e1311827, 10.1080/23723556.2017.1311827 Kaffe, 2017, Hepatocyte autotaxin expression promotes liver fibrosis and cancer, Hepatology, 65, 1369, 10.1002/hep.28973 Oakley, 2009, Angiotensin II activates I kappaB kinase phosphorylation of RelA at Ser 536 to promote myofibroblast survival and liver fibrosis, Gastroenterology, 136, 2334, 10.1053/j.gastro.2009.02.081 Moreno, 2010, Reduction of advanced liver fibrosis by short-term targeted delivery of an angiotensin receptor blocker to hepatic stellate cells in rats, Hepatology, 51, 942 Tamaki, 2013, Angiotensin II type 1 receptor antagonist prevents hepatic carcinoma in rats with nonalcoholic steatohepatitis, J Gastroenterol, 48, 491, 10.1007/s00535-012-0651-7 Facciorusso, 2015, Angiotensin receptor blockers improve survival outcomes after radiofrequency ablation in hepatocarcinoma patients, J Gastroenterol Hepatol, 30, 1643, 10.1111/jgh.12988 Yoshiji, 2009, Combination of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma, J Hepatol, 51, 315, 10.1016/j.jhep.2009.04.011 Yoshiji, 2011, Combination of branched-chain amino acids and angiotensin-converting enzyme inhibitor suppresses the cumulative recurrence of hepatocellular carcinoma: a randomized control trial, Oncol Rep, 26, 1547 Tan, 2016, Peretinoin as an adjuvant therapy for hepatocellular carcinoma, Expert Rev Gastroenterol Hepatol, 10, 1201, 10.1080/17474124.2016.1238303 Okada, 2012, Acyclic retinoid targets platelet-derived growth factor signaling in the prevention of hepatic fibrosis and hepatocellular carcinoma development, Cancer Res, 72, 4459, 10.1158/0008-5472.CAN-12-0028 Guan, 2015, Acyclic retinoid induces differentiation and apoptosis of murine hepatic stem cells, Stem Cell Res Ther, 6, 51, 10.1186/s13287-015-0046-9 Shimakami, 2014, The acyclic retinoid Peretinoin inhibits hepatitis C virus replication and infectious virus release in vitro, Sci Rep, 4, 4688, 10.1038/srep04688 Okada, 2017, Peretinoin, an acyclic retinoid, suppresses steatohepatitis and tumorigenesis by activating autophagy in mice fed an atherogenic high-fat diet, Oncotarget, 8, 39978, 10.18632/oncotarget.18116 Okita, 2015, Survey of survival among patients with hepatitis C virus-related hepatocellular carcinoma treated with peretinoin, an acyclic retinoid, after the completion of a randomized, placebo-controlled trial, J Gastroenterol, 50, 667, 10.1007/s00535-014-0996-1 Lanaya, 2014, EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation, Nat Cell Biol, 16, 971, 10.1038/ncb3031 Komposch, 2016, EGFR signaling in liver diseases, Int J Mol Sci, 17 Fuchs, 2014, Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma, Hepatology, 59, 1577, 10.1002/hep.26898 Bruix, 2015, Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial, Lancet Oncol, 16, 1344, 10.1016/S1470-2045(15)00198-9 Zheng, 2017, Gender disparity in hepatocellular carcinoma (HCC): multiple underlying mechanisms, Sci China Life Sci, 60, 575, 10.1007/s11427-016-9043-9 Sun, 2015, Association between estrogen receptor 1 (ESR1) genetic variations and cancer risk: a meta-analysis, J BUON, 20, 296 Hassan, 2017, Estrogen replacement reduces risk and increases survival times of women with hepatocellular carcinoma, Clin Gastroenterol Hepatol, 15, 1791, 10.1016/j.cgh.2017.05.036 Zheng, 2015, Systemic delivery of microRNA-101 potently inhibits hepatocellular carcinoma in vivo by repressing multiple targets, PLoS Genet, 11, e1004873, 10.1371/journal.pgen.1004873 Wong, 2014, Liver stiffness-based optimization of hepatocellular carcinoma risk score in patients with chronic hepatitis B, J Hepatol, 60, 339, 10.1016/j.jhep.2013.09.029 Yang, 2011, Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score, Lancet Oncol, 12, 568, 10.1016/S1470-2045(11)70077-8 Wong, 2010, Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers, J Clin Oncol, 28, 1660, 10.1200/JCO.2009.26.2675 Yang, 2010, Nomograms for risk of hepatocellular carcinoma in patients with chronic hepatitis B virus infection, J Clin Oncol, 28, 2437, 10.1200/JCO.2009.27.4456 Hung, 2015, Development of risk scoring system for stratifying population for hepatocellular carcinoma screening, Hepatology, 61, 1934, 10.1002/hep.27610 Papatheodoridis, 2016, PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy, J Hepatol, 64, 800, 10.1016/j.jhep.2015.11.035 Sohn, 2017, Risk score model for the development of hepatocellular carcinoma in treatment-naive patients receiving oral antiviral treatment for chronic hepatitis B, Clin Mol Hepatol, 23, 170, 10.3350/cmh.2016.0086 Suh, 2015, High liver fibrosis index FIB-4 is highly predictive of hepatocellular carcinoma in chronic hepatitis B carriers, Hepatology, 61, 1261, 10.1002/hep.27654 Yuen, 2009, Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B, J Hepatol, 50, 80, 10.1016/j.jhep.2008.07.023 Kim, 2015, Increased risk of hepatocellular carcinoma in chronic hepatitis B patients with transient elastography-defined subclinical cirrhosis, Hepatology, 61, 1851, 10.1002/hep.27735 Singal, 2013, Machine learning algorithms outperform conventional regression models in predicting development of hepatocellular carcinoma, Am J Gastroenterol, 108, 1723, 10.1038/ajg.2013.332 Lee, 2014, Development and validation of a clinical scoring system for predicting risk of HCC in asymptomatic individuals seropositive for anti-HCV antibodies, PLoS One, 9, e94760, 10.1371/journal.pone.0094760 Ganne-Carrie, 2016, Nomogram for individualized prediction of hepatocellular carcinoma occurrence in hepatitis C virus cirrhosis (ANRS CO12 CirVir), Hepatology, 64, 1136, 10.1002/hep.28702 Lok, 2009, Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease, Gastroenterology, 136, 138, 10.1053/j.gastro.2008.09.014 El-Serag, 2014, A new laboratory-based algorithm to predict development of hepatocellular carcinoma in patients with hepatitis C and cirrhosis, Gastroenterology, 146, 1249, 10.1053/j.gastro.2014.01.045 Chang, 2013, Clinical-guide risk prediction of hepatocellular carcinoma development in chronic hepatitis C patients after interferon-based therapy, Br J Cancer, 109, 2481, 10.1038/bjc.2013.564 Ikeda, 2005, Risk factors for development of hepatocellular carcinoma in patients with chronic hepatitis C after sustained response to interferon, J Gastroenterol, 40, 148, 10.1007/s00535-004-1519-2 Chang, 2012, A novel predictive score for hepatocellular carcinoma development in patients with chronic hepatitis C after sustained response to pegylated interferon and ribavirin combination therapy, J Antimicrob Chemother, 67, 2766, 10.1093/jac/dks269 Flemming, 2014, Risk prediction of hepatocellular carcinoma in patients with cirrhosis: the ADRESS-HCC risk model, Cancer, 120, 3485, 10.1002/cncr.28832 Velazquez, 2003, Prospective analysis of risk factors for hepatocellular carcinoma in patients with liver cirrhosis, Hepatology, 37, 520, 10.1053/jhep.2003.50093 Aoki, 2017, Prediction of development of hepatocellular carcinoma using a new scoring system involving virtual touch quantification in patients with chronic liver diseases, J Gastroenterol, 52, 104, 10.1007/s00535-016-1228-7 Konerman, 2015, Improvement of predictive models of risk of disease progression in chronic hepatitis C by incorporating longitudinal data, Hepatology, 61, 1832, 10.1002/hep.27750 Lens, 2016, Predicting the development of liver cirrhosis by simple modelling in patients with chronic hepatitis C, Aliment Pharmacol Ther, 43, 364, 10.1111/apt.13472 Vilar-Gomez, 2017, Serum biomarkers can predict a change in liver fibrosis 1 year after lifestyle intervention for biopsy-proven NASH, Liver Int, 10.1111/liv.13480 Irvine, 2016, The Enhanced liver fibrosis score is associated with clinical outcomes and disease progression in patients with chronic liver disease, Liver Int, 36, 370, 10.1111/liv.12896 Simon, 2009, Use of archived specimens in evaluation of prognostic and predictive biomarkers, J Natl Cancer Inst, 101, 1446, 10.1093/jnci/djp335 Wang, 2016, Prospective evidence of a circulating microRNA signature as a non-invasive marker of hepatocellular carcinoma in HBV patients, Oncotarget, 1 Abu Dayyeh, 2011, A functional polymorphism in the epidermal growth factor gene is associated with risk for hepatocellular carcinoma, Gastroenterology, 141, 141, 10.1053/j.gastro.2011.03.045 Guyot, 2013, PNPLA3 rs738409, hepatocellular carcinoma occurrence and risk model prediction in patients with cirrhosis, J Hepatol, 58, 312, 10.1016/j.jhep.2012.09.036 Nahon, 2008, Liver iron, HFE gene mutations, and hepatocellular carcinoma occurrence in patients with cirrhosis, Gastroenterology, 134, 102, 10.1053/j.gastro.2007.10.038 Hoshida, 2008, Gene expression in fixed tissues and outcome in hepatocellular carcinoma, N Engl J Med, 359, 1995, 10.1056/NEJMoa0804525 Hoshida, 2013, Prognostic gene expression signature for patients with hepatitis C-related early-stage cirrhosis, Gastroenterology, 144, 1024, 10.1053/j.gastro.2013.01.021 King, 2015, A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration, Gut, 64, 1296, 10.1136/gutjnl-2014-307862 Zhang, 2016, A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection, Gut, 65, 1754, 10.1136/gutjnl-2015-309655 Ji, 2015, Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma, Hepatology, 62, 481, 10.1002/hep.27822 Kim, 2014, Genomic predictors for recurrence patterns of hepatocellular carcinoma: model derivation and validation, PLoS Med, 11, e1001770, 10.1371/journal.pmed.1001770 Marcolongo, 2009, A seven-gene signature (cirrhosis risk score) predicts liver fibrosis progression in patients with initially mild chronic hepatitis C, Hepatology, 50, 1038, 10.1002/hep.23111 Tateishi, 2008, Diagnostic accuracy of tumor markers for hepatocellular carcinoma: a systematic review, Hepatol Int, 2, 17, 10.1007/s12072-007-9038-x Jia, 2014, Diagnosis accuracy of serum glypican-3 in patients with hepatocellular carcinoma: a systematic review with meta-analysis, Arch Med Res, 45, 580, 10.1016/j.arcmed.2014.11.002 Zhou, 2011, Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma, J Clin Oncol, 29, 4781, 10.1200/JCO.2011.38.2697 Shen, 2012, Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study, Lancet Oncol, 13, 817, 10.1016/S1470-2045(12)70233-4 Zhu, 2013, Evaluation of midkine as a diagnostic serum biomarker in hepatocellular carcinoma, Clin Cancer Res, 19, 3944, 10.1158/1078-0432.CCR-12-3363 Sun, 2013, Annexin A2 is a discriminative serological candidate in early hepatocellular carcinoma, Carcinogenesis, 34, 595, 10.1093/carcin/bgs372 Liu, 2007, N-glycomic changes in hepatocellular carcinoma patients with liver cirrhosis induced by hepatitis B virus, Hepatology, 46, 1426, 10.1002/hep.21855 Shang, 2012, Identification of osteopontin as a novel marker for early hepatocellular carcinoma, Hepatology, 55, 483, 10.1002/hep.24703 Marrero, 2005, GP73, a resident Golgi glycoprotein, is a novel serum marker for hepatocellular carcinoma, J Hepatol, 43, 1007, 10.1016/j.jhep.2005.05.028 Wang, 2017, Changes in the glycosylation of kininogen and the development of a kininogen-based algorithm for the early detection of HCC, Cancer Epidemiol Biomarkers Prev, 26, 795, 10.1158/1055-9965.EPI-16-0974