Download PDF
Semin Liver Dis 2019; 39(02): 153-162
DOI: 10.1055/s-0039-1681031
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Hepatocellular Carcinoma Risk Stratification by Genetic Profiling in Patients with Cirrhosis

Naoto Fujiwara
1   Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
2   Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
,
Yujin Hoshida
1   Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
› Author Affiliations Funding This work is supported by Uehara Memorial Foundation (to N.F.) and U.S. NIH/NIDDK R01 DK099558, European Union ERC-2014-AdG-671231 HEPCIR, Irma T. Hirschl Trust, U.S. Department of Defense W81XWH-16-1-0363, and Cancer Prevention and Research Institute of Texas RR180016 (to Y.H.).
Further Information

Publication History

Publication Date:
25 March 2019 (online)

    Permissions and Reprints

Abstract

Prediction of future hepatocellular carcinoma (HCC) risk in the sizable chronic liver disease population is an urgent unmet need to enable regular HCC screening for early detection. Germline deoxyribonucleic acid polymorphisms likely represent etiology-specific host factors that determine HCC susceptibility, including single nucleotide polymorphisms in EGF, IFNL3, MICA, and TLL1 in hepatitis C with or without active viral infection, and PNPLA3, TM6SF2, and MBOAT7 in metabolic liver diseases. Transcriptome-based prognostic liver signature in diseased liver tissue has been associated with long-term HCC risk in viral and metabolic etiologies. Transcriptomic signatures of hepatic injury and specific cell type such as aggregated lymphocytes also predict HCC development. Circulating factors such as proteins and their chemical modification, nucleotides, and metabolites may serve for less-invasive assessment of short- or long-term HCC risk. These biomarkers will enable individual HCC risk-based personalized clinical management for cost-effective early HCC detection and improvement of patient survival.

Keywords

risk prediction - cirrhosis - hepatocellular carcinoma - precision medicine
 

  • References

  • 1 Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol 2018; 68 (03) 526-549
    CrossrefPubMedGoogle Scholar
  • 2 Petrick JL, Kelly SP, Altekruse SF, McGlynn KA, Rosenberg PS. Future of hepatocellular carcinoma incidence in the United States forecast through 2030. J Clin Oncol 2016; 34 (15) 1787-1794
    CrossrefPubMedGoogle Scholar
  • 3 Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65 (02) 87-108
    CrossrefPubMedGoogle Scholar
  • 4 Bertuccio P, Turati F, Carioli G. , et al. Global trends and predictions in hepatocellular carcinoma mortality. J Hepatol 2017; 67 (02) 302-309
    CrossrefPubMedGoogle Scholar
  • 5 Yang JD, Mohamed EA, Aziz AO. , et al; Africa Network for Gastrointestinal and Liver Diseases. Characteristics, management, and outcomes of patients with hepatocellular carcinoma in Africa: a multicountry observational study from the Africa Liver Cancer Consortium. Lancet Gastroenterol Hepatol 2017; 2 (02) 103-111
    CrossrefPubMedGoogle Scholar
  • 6 Marrero JA, Kulik LM, Sirlin CB. , et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 2018; 68 (02) 723-750
    CrossrefPubMedGoogle Scholar
  • 7 Tzartzeva K, Obi J, Rich NE. , et al. Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis. Gastroenterology 2018; 154 (06) 1706-1718.e1
    CrossrefPubMedGoogle Scholar
  • 8 Cadier B, Bulsei J, Nahon P. , et al; ANRS CO12 CirVir and CHANGH groups. Early detection and curative treatment of hepatocellular carcinoma: a cost-effectiveness analysis in France and in the United States. Hepatology 2017; 65 (04) 1237-1248
    CrossrefPubMedGoogle Scholar
  • 9 Mortality GBD. ; GBD 2013 Mortality and Causes of Death Collaborators. 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 2015; 385 (9963): 117-171
    CrossrefPubMedGoogle Scholar
  • 10 Singal AG, El-Serag HB. Hepatocellular carcinoma from epidemiology to prevention: translating knowledge into practice. Clin Gastroenterol Hepatol 2015; 13 (12) 2140-2151
    CrossrefPubMedGoogle Scholar
  • 11 Singal AG, Tiro JA, Marrero JA. , et al. Mailed outreach program increases ultrasound screening of patients with cirrhosis for hepatocellular carcinoma. Gastroenterology 2017; 152 (03) 608-615.e4
    CrossrefPubMedGoogle Scholar
  • 12 Singal AG, Tiro JA, Murphy CC. , et al. Mailed outreach invitations significantly improve HCC surveillance rates in patients with cirrhosis: a randomized clinical trial. Hepatology 2018 Doi: 10.1002/hep.30129
    PubMedGoogle Scholar
  • 13 Santi V, Trevisani F, Gramenzi A. , et al; Italian Liver Cancer (ITA.LI.CA) Group. Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival. J Hepatol 2010; 53 (02) 291-297
    CrossrefPubMedGoogle Scholar
  • 14 Trinchet JC, Chaffaut C, Bourcier V. , et al; Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire (GRETCH). Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities. Hepatology 2011; 54 (06) 1987-1997
    CrossrefPubMedGoogle Scholar
  • 15 Goossens N, Bian CB, Hoshida Y. Tailored algorithms for hepatocellular carcinoma surveillance: is one-size-fits-all strategy outdated?. Curr Hepatol Rep 2017; 16 (01) 64-71
    PubMedGoogle Scholar
  • 16 Tanabe KK, Lemoine A, Finkelstein DM. , et al. Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis. JAMA 2008; 299 (01) 53-60
    PubMedGoogle Scholar
  • 17 Abu Dayyeh BK, Yang M, Fuchs BC. , et al; HALT-C Trial Group. A functional polymorphism in the epidermal growth factor gene is associated with risk for hepatocellular carcinoma. Gastroenterology 2011; 141 (01) 141-149
    CrossrefPubMedGoogle Scholar
  • 18 Jiang G, Yu K, Shao L. , et al. Association between epidermal growth factor gene +61A/G polymorphism and the risk of hepatocellular carcinoma: a meta-analysis based on 16 studies. BMC Cancer 2015; 15: 314
    CrossrefPubMedGoogle Scholar
  • 19 Asahina Y, Tsuchiya K, Nishimura T. , et al. Genetic variation near interleukin 28B and the risk of hepatocellular carcinoma in patients with chronic hepatitis C. J Gastroenterol 2014; 49 (07) 1152-1162
    CrossrefPubMedGoogle Scholar
  • 20 Chang KC, Tseng PL, Wu YY. , et al. A polymorphism in interferon L3 is an independent risk factor for development of hepatocellular carcinoma after treatment of hepatitis C virus infection. Clin Gastroenterol Hepatol 2015; 13 (05) 1017-1024
    CrossrefPubMedGoogle Scholar
  • 21 Hodo Y, Honda M, Tanaka A. , et al. Association of interleukin-28B genotype and hepatocellular carcinoma recurrence in patients with chronic hepatitis C. Clin Cancer Res 2013; 19 (07) 1827-1837
    CrossrefPubMedGoogle Scholar
  • 22 Kumar V, Kato N, Urabe Y. , et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet 2011; 43 (05) 455-458
    CrossrefPubMedGoogle Scholar
  • 23 Tong HV, Toan NL, Song LH, Bock CT, Kremsner PG, Velavan TP. Hepatitis B virus-induced hepatocellular carcinoma: functional roles of MICA variants. J Viral Hepat 2013; 20 (10) 687-698
    CrossrefPubMedGoogle Scholar
  • 24 Miki D, Ochi H, Hayes CN. , et al. Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers. Nat Genet 2011; 43 (08) 797-800
    CrossrefPubMedGoogle Scholar
  • 25 Matsuura K, Sawai H, Ikeo K. , et al; Japanese Genome-Wide Association Study Group for Viral Hepatitis. Genome-wide association study identifies TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus infection. Gastroenterology 2017; 152 (06) 1383-1394
    CrossrefPubMedGoogle Scholar
  • 26 Zhang H, Zhai Y, Hu Z. , et al. Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers. Nat Genet 2010; 42 (09) 755-758
    CrossrefPubMedGoogle Scholar
  • 27 Jiang DK, Sun J, Cao G. , et al. Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma. Nat Genet 2013; 45 (01) 72-75
    CrossrefPubMedGoogle Scholar
  • 28 Chen K, Shi W, Xin Z. , et al. Replication of genome wide association studies on hepatocellular carcinoma susceptibility loci in a Chinese population. PLoS One 2013; 8 (10) e77315
    CrossrefPubMedGoogle Scholar
  • 29 Guyot E, Sutton A, Rufat P. , et al. PNPLA3 rs738409, hepatocellular carcinoma occurrence and risk model prediction in patients with cirrhosis. J Hepatol 2013; 58 (02) 312-318
    CrossrefPubMedGoogle Scholar
  • 30 Liu YL, Patman GL, Leathart JB. , et al. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol 2014; 61 (01) 75-81
    CrossrefPubMedGoogle Scholar
  • 31 Falleti E, Fabris C, Cmet S. , et al. PNPLA3 rs738409C/G polymorphism in cirrhosis: relationship with the aetiology of liver disease and hepatocellular carcinoma occurrence. Liver Int 2011; 31 (08) 1137-1143
    CrossrefPubMedGoogle Scholar
  • 32 Stickel F, Buch S, Nischalke HD. , et al. Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis. Am J Gastroenterol 2018; 113 (10) 1475-1483
    CrossrefPubMedGoogle Scholar
  • 33 Falleti E, Cussigh A, Cmet S, Fabris C, Toniutto P. PNPLA3 rs738409 and TM6SF2 rs58542926 variants increase the risk of hepatocellular carcinoma in alcoholic cirrhosis. Dig Liver Dis 2016; 48 (01) 69-75
    CrossrefPubMedGoogle Scholar
  • 34 Donati B, Dongiovanni P, Romeo S. , et al. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci Rep 2017; 7 (01) 4492
    CrossrefPubMedGoogle Scholar
  • 35 Nahon P, Sutton A, Rufat P. , et al. A variant in myeloperoxidase promoter hastens the emergence of hepatocellular carcinoma in patients with HCV-related cirrhosis. J Hepatol 2012; 56 (02) 426-432
    CrossrefPubMedGoogle Scholar
  • 36 Nahon P, Sutton A, Rufat P. , et al. Liver iron, HFE gene mutations, and hepatocellular carcinoma occurrence in patients with cirrhosis. Gastroenterology 2008; 134 (01) 102-110
    CrossrefPubMedGoogle Scholar
  • 37 Hoshida Y, Villanueva A, Sangiovanni A. , et al. Prognostic gene expression signature for patients with hepatitis C-related early-stage cirrhosis. Gastroenterology 2013; 144 (05) 1024-1030
    CrossrefPubMedGoogle Scholar
  • 38 King LY, Canasto-Chibuque C, Johnson KB. , et al. A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration. Gut 2015; 64 (08) 1296-1302
    CrossrefPubMedGoogle Scholar
  • 39 Nakagawa S, Wei L, Song WM. , et al; Precision Liver Cancer Prevention Consortium. Molecular liver cancer prevention in cirrhosis by organ transcriptome analysis and lysophosphatidic acid pathway inhibition. Cancer Cell 2016; 30 (06) 879-890
    CrossrefPubMedGoogle Scholar
  • 40 Kim JH, Sohn BH, Lee HS. , et al. Genomic predictors for recurrence patterns of hepatocellular carcinoma: model derivation and validation. PLoS Med 2014; 11 (12) e1001770
    CrossrefPubMedGoogle Scholar
  • 41 Finkin S, Yuan D, Stein I. , et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat Immunol 2015; 16 (12) 1235-1244
    CrossrefPubMedGoogle Scholar
  • 42 Ji J, Eggert T, Budhu A. , et al. Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma. Hepatology 2015; 62 (02) 481-495
    CrossrefPubMedGoogle Scholar
  • 43 Zhang DY, Goossens N, Guo J. , et al. A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection. Gut 2016; 65 (10) 1754-1764
    CrossrefPubMedGoogle Scholar
  • 44 Nakagawa H, Maeda S, Yoshida H. , et al. Serum IL-6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: an analysis based on gender differences. Int J Cancer 2009; 125 (10) 2264-2269
    CrossrefPubMedGoogle Scholar
  • 45 Ohishi W, Cologne JB, Fujiwara S. , et al. Serum interleukin-6 associated with hepatocellular carcinoma risk: a nested case-control study. Int J Cancer 2014; 134 (01) 154-163
    CrossrefPubMedGoogle Scholar
  • 46 Aleksandrova K, Boeing H, Nöthlings U. , et al. Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer. Hepatology 2014; 60 (03) 858-871
    CrossrefPubMedGoogle Scholar
  • 47 Mazziotti G, Sorvillo F, Morisco F. , et al. 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 2002; 95 (12) 2539-2545
    CrossrefPubMedGoogle Scholar
  • 48 Cho EJ, Lee JH, Yoo JJ. , et al. Serum insulin-like growth factor-I level is an independent predictor of recurrence and survival in early hepatocellular carcinoma: a prospective cohort study. Clin Cancer Res 2013; 19 (15) 4218-4227
    CrossrefPubMedGoogle Scholar
  • 49 Callewaert N, Van Vlierberghe H, Van Hecke A, Laroy W, Delanghe J, Contreras R. Noninvasive diagnosis of liver cirrhosis using DNA sequencer-based total serum protein glycomics. Nat Med 2004; 10 (04) 429-434
    CrossrefPubMedGoogle Scholar
  • 50 Wang C, Hann H-W, Ye Z. , et al. Prospective evidence of a circulating microRNA signature as a non-invasive marker of hepatocellular carcinoma in HBV patients. Oncotarget 2016;1–16
    PubMedGoogle Scholar
  • 51 Nahon P, Zucman-Rossi J. Single nucleotide polymorphisms and risk of hepatocellular carcinoma in cirrhosis. J Hepatol 2012; 57 (03) 663-674
    CrossrefPubMedGoogle Scholar
  • 52 Mueller JL, King LY, Johnson KB. , et al. Impact of EGF, IL28B, and PNPLA3 polymorphisms on the outcome of allograft hepatitis C: a multicenter study. Clin Transplant 2016; 30 (04) 452-460
    CrossrefPubMedGoogle Scholar
  • 53 Fuchs BC, Hoshida Y, Fujii T. , et al. Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma. Hepatology 2014; 59 (04) 1577-1590
    CrossrefPubMedGoogle Scholar
  • 54 Lanaya H, Natarajan A, Komposch K. , et al. EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation. Nat Cell Biol 2014; 16 (10) 972-977
    CrossrefPubMedGoogle Scholar
  • 55 Thomas DL, Thio CL, Martin MP. , et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009; 461 (7265): 798-801
    PubMedGoogle Scholar
  • 56 Suppiah V, Moldovan M, Ahlenstiel G. , et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet 2009; 41 (10) 1100-1104
    CrossrefPubMedGoogle Scholar
  • 57 Tanaka Y, Nishida N, Sugiyama M. , et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 2009; 41 (10) 1105-1109
    CrossrefPubMedGoogle Scholar
  • 58 Ge D, Fellay J, Thompson AJ. , et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461 (7262): 399-401
    PubMedGoogle Scholar
  • 59 Eslam M, McLeod D, Kelaeng KS. , et al; International Liver Disease Genetics Consortium (ILDGC). IFN-λ3, not IFN-λ4, likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis. Nat Genet 2017; 49 (05) 795-800
    CrossrefPubMedGoogle Scholar
  • 60 Hai H, Tamori A, Thuy LTT. , et al. Polymorphisms in MICA, but not in DEPDC5, HCP5 or PNPLA3, are associated with chronic hepatitis C-related hepatocellular carcinoma. Sci Rep 2017; 7 (01) 11912
    CrossrefPubMedGoogle Scholar
  • 61 Huang CF, Huang CY, Yeh ML. , et al. Genetics variants and serum levels of MHC Class I chain-related A in predicting hepatocellular carcinoma development in chronic hepatitis C patients post antiviral treatment. EBioMedicine 2017; 15: 81-89
    CrossrefPubMedGoogle Scholar
  • 62 Lange CM, Bibert S, Dufour JF. , et al; Swiss Hepatitis C Cohort Study Group. Comparative genetic analyses point to HCP5 as susceptibility locus for HCV-associated hepatocellular carcinoma. J Hepatol 2013; 59 (03) 504-509
    CrossrefPubMedGoogle Scholar
  • 63 Burza MA, Motta BM, Mancina RM. , et al. DEPDC5 variants increase fibrosis progression in Europeans with chronic hepatitis C virus infection. Hepatology 2016; 63 (02) 418-427
    CrossrefPubMedGoogle Scholar
  • 64 Baumert TF, Jühling F, Ono A, Hoshida Y. Hepatitis C-related hepatocellular carcinoma in the era of new generation antivirals. BMC Med 2017; 15 (01) 52
    CrossrefPubMedGoogle Scholar
  • 65 Waziry R, Hajarizadeh B, Grebely J. , et al. Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression. J Hepatol 2017; 67 (06) 1204-1212
    CrossrefPubMedGoogle Scholar
  • 66 Seko Y, Yamaguchi K, Mizuno N. , et al. Combination of PNPLA3 and TLL1 polymorphism can predict advanced fibrosis in Japanese patients with nonalcoholic fatty liver disease. J Gastroenterol 2018; 53 (03) 438-448
    CrossrefPubMedGoogle Scholar
  • 67 Petrick JL, Braunlin M, Laversanne M, Valery PC, Bray F, McGlynn KA. International trends in liver cancer incidence, overall and by histologic subtype, 1978-2007. Int J Cancer 2016; 139 (07) 1534-1545
    CrossrefPubMedGoogle Scholar
  • 68 Sawai H, Nishida N, Mbarek H. , et al. No association for Chinese HBV-related hepatocellular carcinoma susceptibility SNP in other East Asian populations. BMC Med Genet 2012; 13: 47
    PubMedGoogle Scholar
  • 69 Sopipong W, Tangkijvanich P, Payungporn S, Posuwan N, Poovorawan Y. The KIF1B (rs17401966) single nucleotide polymorphism is not associated with the development of HBV-related hepatocellular carcinoma in Thai patients. Asian Pac J Cancer Prev 2013; 14 (05) 2865-2869
    CrossrefPubMedGoogle Scholar
  • 70 Cao P, Yang A, Wang R. , et al. Germline duplication of SNORA18L5 increases risk for HBV-related hepatocellular carcinoma by altering localization of ribosomal proteins and decreasing levels of p53. Gastroenterology 2018; 155 (02) 542-556
    CrossrefPubMedGoogle Scholar
  • 71 Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease - meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64 (01) 73-84
    CrossrefPubMedGoogle Scholar
  • 72 Fujiwara N, Nakagawa H, Kudo Y. , et al. Sarcopenia, intramuscular fat deposition, and visceral adiposity independently predict the outcomes of hepatocellular carcinoma. J Hepatol 2015; 63 (01) 131-140
    CrossrefPubMedGoogle Scholar
  • 73 La Vecchia C, Bosetti C, Bertuccio P, Castro C, Pelucchi C, Negri E. Trends in alcohol consumption in Europe and their impact on major alcohol-related cancers. Eur J Cancer Prev 2014; 23 (04) 319-322
    CrossrefPubMedGoogle Scholar
  • 74 Romeo S, Kozlitina J, Xing C. , et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40 (12) 1461-1465
    CrossrefPubMedGoogle Scholar
  • 75 Valenti L, Rumi M, Galmozzi E. , et al. Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C. Hepatology 2011; 53 (03) 791-799
    CrossrefPubMedGoogle Scholar
  • 76 Burza MA, Molinaro A, Attilia ML. , et al. PNPLA3 I148M (rs738409) genetic variant and age at onset of at-risk alcohol consumption are independent risk factors for alcoholic cirrhosis. Liver Int 2014; 34 (04) 514-520
    CrossrefPubMedGoogle Scholar
  • 77 Rotman Y, Koh C, Zmuda JM, Kleiner DE, Liang TJ. , NASH CRN. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 2010; 52 (03) 894-903
    CrossrefPubMedGoogle Scholar
  • 78 Trépo E, Romeo S, Zucman-Rossi J, Nahon P. PNPLA3 gene in liver diseases. J Hepatol 2016; 65 (02) 399-412
    CrossrefPubMedGoogle Scholar
  • 79 BasuRay S, Smagris E, Cohen JC, Hobbs HH. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology 2017; 66 (04) 1111-1124
    CrossrefPubMedGoogle Scholar
  • 80 Stender S, Kozlitina J, Nordestgaard BG, Tybjærg-Hansen A, Hobbs HH, Cohen JC. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat Genet 2017; 49 (06) 842-847
    CrossrefPubMedGoogle Scholar
  • 81 Fracanzani AL, Petta S, Lombardi R. , et al. Liver and cardiovascular damage in patients with lean nonalcoholic fatty liver disease, and association with visceral obesity. Clin Gastroenterol Hepatol 2017; 15 (10) 1604-1611.e1
    CrossrefPubMedGoogle Scholar
  • 82 Singal AG, Manjunath H, Yopp AC. , et al. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol 2014; 109 (03) 325-334
    CrossrefPubMedGoogle Scholar
  • 83 Trépo E, Nahon P, Bontempi G. , et al. Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: evidence from a meta-analysis of individual participant data. Hepatology 2014; 59 (06) 2170-2177
    CrossrefPubMedGoogle Scholar
  • 84 Brouwer WP, van der Meer AJ, Boonstra A. , et al. The impact of PNPLA3 (rs738409 C>G) polymorphisms on liver histology and long-term clinical outcome in chronic hepatitis B patients. Liver Int 2015; 35 (02) 438-447
    CrossrefPubMedGoogle Scholar
  • 85 Ali M, Yopp A, Gopal P. , et al. A variant in PNPLA3 associated with fibrosis progression but not hepatocellular carcinoma in patients with hepatitis C virus infection. Clin Gastroenterol Hepatol 2016; 14 (02) 295-300
    CrossrefPubMedGoogle Scholar
  • 86 Salomao M, Remotti H, Vaughan R, Siegel AB, Lefkowitch JH, Moreira RK. The steatohepatitic variant of hepatocellular carcinoma and its association with underlying steatohepatitis. Hum Pathol 2012; 43 (05) 737-746
    CrossrefPubMedGoogle Scholar
  • 87 Fujiwara N, Nakagawa H, Enooku K. , et al. CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity. Gut 2018; 67 (08) 1493-1504
    CrossrefPubMedGoogle Scholar
  • 88 Tan PS, Nakagawa S, Goossens N. , et al. Clinicopathological indices to predict hepatocellular carcinoma molecular classification. Liver Int 2016; 36 (01) 108-118
    CrossrefPubMedGoogle Scholar
  • 89 Chan AW, Yu S, Yu YH. , et al. Steatotic hepatocellular carcinoma: a variant associated with metabolic factors and late tumour relapse. Histopathology 2016; 69 (06) 971-984
    CrossrefPubMedGoogle Scholar
  • 90 Mahdessian H, Taxiarchis A, Popov S. , et al. TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content. Proc Natl Acad Sci U S A 2014; 111 (24) 8913-8918
    CrossrefPubMedGoogle Scholar
  • 91 O'Hare EA, Yang R, Yerges-Armstrong LM. , et al. TM6SF2 rs58542926 impacts lipid processing in liver and small intestine. Hepatology 2017; 65 (05) 1526-1542
    CrossrefPubMedGoogle Scholar
  • 92 Fan Y, Lu H, Guo Y. , et al. Hepatic transmembrane 6 superfamily member 2 regulates cholesterol metabolism in mice. Gastroenterology 2016; 150 (05) 1208-1218
    CrossrefPubMedGoogle Scholar
  • 93 Kozlitina J, Smagris E, Stender S. , et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2014; 46 (04) 352-356
    CrossrefPubMedGoogle Scholar
  • 94 Buch S, Stickel F, Trépo E. , et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat Genet 2015; 47 (12) 1443-1448
    CrossrefPubMedGoogle Scholar
  • 95 Eslam M, Mangia A, Berg T. , et al; International Liver Disease Genetics Consortium. Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes. Hepatology 2016; 64 (01) 34-46
    CrossrefPubMedGoogle Scholar
  • 96 Liu YL, Reeves HL, Burt AD. , et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun 2014; 5: 4309
    CrossrefPubMedGoogle Scholar
  • 97 Mancina RM, Dongiovanni P, Petta S. , et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology 2016; 150 (05) 1219-1230.e6
    CrossrefPubMedGoogle Scholar
  • 98 Freedman ND, Cross AJ, McGlynn KA. , et al. Association of meat and fat intake with liver disease and hepatocellular carcinoma in the NIH-AARP cohort. J Natl Cancer Inst 2010; 102 (17) 1354-1365
    CrossrefPubMedGoogle Scholar
  • 99 Kawaguchi T, Shima T, Mizuno M. , et al. Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers. PLoS One 2018; 13 (01) e0185490
    CrossrefPubMedGoogle Scholar
  • 100 Abul-Husn NS, Cheng X, Li AH. , et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med 2018; 378 (12) 1096-1106
    CrossrefPubMedGoogle Scholar
  • 101 Chen J, Zhuo JY, Yang F. , et al. 17-beta-hydroxysteroid dehydrogenase 13 inhibits the progression and recurrence of hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2018; 17 (03) 220-226
    CrossrefPubMedGoogle Scholar
  • 102 Ono A, Goossens N, Finn RS. , et al; Precision Liver Cancer Prevention Consortium. Persisting risk of hepatocellular carcinoma after hepatitis C virus cure monitored by a liver transcriptome signature. Hepatology 2017; 66 (04) 1344-1346
    CrossrefPubMedGoogle Scholar
  • 103 Hoshida Y, Villanueva A, Kobayashi M. , et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med 2008; 359 (19) 1995-2004
    CrossrefPubMedGoogle Scholar
  • 104 Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev 2017; 121: 27-42
    CrossrefPubMedGoogle Scholar
  • 105 Goossens N, Nakagawa S, Sun X, Hoshida Y. Cancer biomarker discovery and validation. Transl Cancer Res 2015; 4 (03) 256-269
    PubMedGoogle Scholar
  • 106 Duarte-Salles T, Misra S, Stepien M. , et al. Circulating osteopontin and prediction of hepatocellular carcinoma development in a large European population. Cancer Prev Res (Phila) 2016; 9 (09) 758-765
    CrossrefPubMedGoogle Scholar
  • 107 He G, Dhar D, Nakagawa H. , et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 2013; 155 (02) 384-396
    CrossrefPubMedGoogle Scholar
  • 108 Debes JD, van Tilborg M, Groothuismink ZMA. , et al. Levels of cytokines in serum associate with development of hepatocellular carcinoma in patients with HCV infection treated with direct-acting antivirals. Gastroenterology 2018; 154 (03) 515-517.e3
    CrossrefPubMedGoogle Scholar
  • 109 Verhelst X, Vanderschaeghe D, Castéra L. , et al. A glycomics-based test predicts the development of hepatocellular carcinoma in cirrhosis. Clin Cancer Res 2017; 23 (11) 2750-2758
    CrossrefPubMedGoogle Scholar
  • 110 Sun C, Liao W, Deng Z. , et al. The diagnostic value of assays for circulating tumor cells in hepatocellular carcinoma: a meta-analysis. Medicine (Baltimore) 2017; 96 (29) e7513
    PubMedGoogle Scholar
  • 111 Xu RH, Wei W, Krawczyk M. , et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. Nat Mater 2017; 16 (11) 1155-1161
    CrossrefPubMedGoogle Scholar
  • 112 Zhu S, Hoshida Y. Molecular heterogeneity in hepatocellular carcinoma. Hepat Oncol 2018; 5 (01) HEP10
    PubMedGoogle Scholar
  • 113 Huang A, Zhao X, Yang XR. , et al. Circumventing intratumoral heterogeneity to identify potential therapeutic targets in hepatocellular carcinoma. J Hepatol 2017; 67 (02) 293-301
    CrossrefPubMedGoogle Scholar
  • 114 Sun YF, Guo W, Xu Y. , et al. Circulating tumor cells from different vascular sites exhibit spatial heterogeneity in epithelial and mesenchymal composition and distinct clinical significance in hepatocellular carcinoma. Clin Cancer Res 2018; 24 (03) 547-559
    CrossrefPubMedGoogle Scholar
  • 115 Cohen JD, Li L, Wang Y. , et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science 2018; 359 (6378): 926-930
    CrossrefPubMedGoogle Scholar
  • 116 Qi LN, Xiang BD, Wu FX. , et al. Circulating tumor cells undergoing EMT provide a metric for diagnosis and prognosis of patients with hepatocellular carcinoma. Cancer Res 2018; 78 (16) 4731-4744
    CrossrefPubMedGoogle Scholar
  • 117 Court CM, Hou S, Winograd P. , et al. A novel multimarker assay for the phenotypic profiling of circulating tumor cells in hepatocellular carcinoma. Liver Transpl 2018; 24 (07) 946-960
    CrossrefPubMedGoogle Scholar
  • 118 Hann HW, Jain S, Park G, Steffen JD, Song W, Su YH. Detection of urine DNA markers for monitoring recurrent hepatocellular carcinoma. Hepatoma Res 2017; 3: 105-111
    CrossrefPubMedGoogle Scholar
  • 119 Jiao J, Watt GP, Stevenson HL. , et al. Telomerase reverse transcriptase mutations in plasma DNA in patients with hepatocellular carcinoma or cirrhosis: prevalence and risk factors. Hepatol Commun 2018; 2 (06) 718-731
    CrossrefPubMedGoogle Scholar
  • 120 Goossens N, Singal AG, King LY. , et al. Cost-effectiveness of risk score-stratified hepatocellular carcinoma screening in patients with cirrhosis. Clin Transl Gastroenterol 2017; 8 (06) e101
    CrossrefPubMedGoogle Scholar
  • 121 European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2018; 69 (01) 182-236
    CrossrefPubMedGoogle Scholar