Novel predictive and prognostic strategies of hepatitis B virus related hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a common malignancy and an important cause of cancer death worldwide. Chronic hepatitis B virus (HBV) infection is the major cause of HCC. Recent studies of HBV-induced carcinogenesis not only discovered many new biomarkers but also developed a novel theory: Cancer Evolution-Development (Cancer Evo-Dev). Cancer Evo-Dev provides an evolutionary insight of developing more reasonable predictive and prognostic strategies. Characterizing chronic inflammatory microenvironment of cancer evolution, genetic polymorphisms of inflammatory factors, and HCC-related HBV mutations that negatively selected by host immunity may help greatly in identifying HBV-infected individuals who are more likely to develop HCC or benefit from HCC prophylactic options. Gene expression signatures and somatic mutation profiles reflect the different patterns of signaling pathway networks underlying tumor heterogeneity and can be applied to improve the molecular classification and prognostic stratification of HCC patients. Mutant cells that survive the selection can retro-differentiate into tumor initial cells and aggressive sub-clones. Detection of mutants or their hallmarks in cell-free DNA in peripheral blood potentially improve the early diagnosis, prognosis prediction, and personalized treatment of HBV-caused HCC.

Keywords

Hepatocellular carcinoma / hepatitis B virus / evolution / prediction / prognosis

References

[1] Torre LA,Ferlay J,Jemal A.Global cancer statistics, 2012..CA Cancer J Clin2015;65:87-108

[2] Nguyen VT,Dore GJ.Hepatitis B-related hepatocellular carcinoma: epidemiological characteristics and disease burden..J Viral Hepat2009;16:453-63

[3] Lavanchy D.Worldwide epidemiology of HBV infection, disease burden, and vaccine prevention..J Clin Virol2005;34 Suppl 1:S1-3

[4] E-Serag HB.Epidemiology of viral hepatitis and hepatocellular carcinoma..Gastroenterology2012;142:1264-73

[5] Huang YT,Yang HI,Su J,Iloeje UH.Lifetime risk and sex difference of hepatocellular carcinoma among patients with chronic hepatitis B and C..J Clin Oncol2011;29:3643-50 PMCID:PMC4874144

[6] Sharma S,Feld JJ.Immigration and viral hepatitis..J Hepatol2015;63:515-22

[7] Du Y,Ding Y.Effects of antiviral therapy on the recurrence of hepatocellular carcinoma after curative resection or liver transplantation..Hepat Mon2012;12:e6031

[8] Hyder O,Pulitano C,Alexandrescu S,Gamblin TC,Paul A,Clary BM,Ferrone CR,Popescu I,Mentha G,Pawlik TM.A nomogram to predict long-term survival after resection for intrahepatic cholangiocarcinoma: an Eastern and Western experience..JAMA Surg2014;149:432-8

[9] Liu WB,DuY.Cancer Evolution-Development: experience of hepatitis B virus-induced hepatocarcinogenesis..Curr Oncol2016;23:e49-56

[10] Li ZX,Ni HX,Lu W,Liu WB,Zhao Y,Pu R,Dong HJ,Sun Q,Cao GW.Mother-to-child transmission of hepatitis B virus: evolution of hepatocellular carcinoma-related viral mutations in the post-immunization era..J Clin Virol2014;61:47-54

[11] Liu S,Gu C,He Y,Cao G.Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis..J Natl Cancer Inst2009;101:1066-82 PMCID:PMC2720989

[12] Xie J,Zhang Q,Yin J,Shen Q,Du Y,Han X,Cao G.Interaction of signal transducer and activator of transcription 3 polymorphisms with hepatitis B virus mutations in hepatocellular carcinoma..Hepatology2013;57:2369-77

[13] Yin J,Han Y,Deng Y,Guo W,Wang H,Cao G.Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study..J Clin Oncol2013;31:3647-55

[14] Yin J,Liu S,Han L,Shen Q,Dong H,Zhang J,Wang L,Wang F,Zhang Q,Wang H.Association between the various mutations in viral core promoter region to different stages of hepatitis B, ranging of asymptomatic carrier state to hepatocellular carcinoma..Am J Gastroenterol2011;106:81-92

[15] Yin J,Zhang H,Han L,Han Y,Ni W,Cao G.Significant association of different preS mutations with hepatitis B-related cirrhosis or hepatocellular carcinoma..J Gastroenterol2010;45:1063-71

[16] Zhang HW,Li YT,Ren H,Wu HY,Zhang P,Tan XJ,Schaefer S.Risk factors for acute hepatitis B and its progression to chronic hepatitis in Shanghai, China..Gut2008;57:1713-20

[17] Zhang Q,Hou XM,DuY,Sun XY,Zhao J,Yang GS,Chen XM,Wang HY.Effect of functional nuclear factor-kappaB genetic polymorphisms on hepatitis B virus persistence and their interactions with viral mutations on the risk of hepatocellular carcinoma..Ann Oncol2014;25:2413-9

[18] Zhang Q,Zhang Y,Ji X,Pu R,Zhao J,Zhang H.HLA-DP polymorphisms affect the outcomes of chronic hepatitis B virus infections, possibly through interacting with viral mutations..J Virol2013;87:12176-86 PMCID:PMC3807892

[19] Alexandrov LB,Wedge DC,Behjati S,Bignell GR,Borg A,Boyault S,Butler AP,Davies HR,Eils R,Foekens JA,Hosoda F,Ilicic T,Imielinski M,Jones DT,Knappskog S,Lakhani SR,Martin S,Nakamura H,Pajic M,Paradiso A,Puente XS,Ramakrishna M,Richter J,Schlesner M,Span PN,Totoki Y,Valdes-Mas R,Laura van 't Veer,Waddell N,Australian Pancreatic Cancer Genome I,Consortium I M-S,Zucman-Rossi J,McDermott U,Meyerson M,Siebert R,Shibata T,Campbell PJ.Signatures of mutational processes in human cancer..Nature2013;500:415-21

[20] Stratton MR,Futreal PA.The cancer genome..Nature2009;458:719-24

[21] Chan HL,Mo F,Wong VW,Chan SL,Sung JJ.High viral load and hepatitis B virus subgenotype ce are associated with increased risk of hepatocellular carcinoma..J Clin Oncol2008;26:177-82

[22] Yang HI,Chan HL,Chen PJ,Ahn SH,Wong VW.Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score..Lancet Oncol2011;12:568-74

[23] Lee MH,Liu J,Jen CL,Lu SN,Wang LY.Prediction models of long-term cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B patients: risk scores integrating host and virus profiles..Hepatology2013;58:546-54

[24] Yeh CT,Ng J,Chang ML,Chen TC,Yeh T S.Hepatitis B virus-DNA level and basal core promoter A1762T/G1764A mutation in liver tissue independently predict postoperative survival in hepatocellular carcinoma..Hepatology2010;52:1922-33

[25] Yang HI,Liaw YF,Sun CA,Hsiao CK,Chen DS.Hepatitis B e antigen and the risk of hepatocellular carcinoma..N Engl J Med2002;347:168-74

[26] Norder H,Coursaget P,Lee SD,Robertson BH,Magnius LO.Genetic diversity of hepatitis B virus strains derived worldwide: genotypes, subgenotypes, and HBsAg subtypes..Intervirology2004;47:289-309

[27] Yin J,He Y,Liu S,Tan X,Lu W,Bi S,Liang X,Cao G.Distribution and hepatocellular carcinoma-related viral properties of hepatitis B virus genotypes in Mainland China: a community-based study..Cancer Epidemiol Biomarkers Prev2010;19:777-86

[28] Chan HL,Wong ML,Hung LC,Sung JJ.Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma..Gut2004;53:1494-98 PMCID:PMC1774221

[29] Yu MW,Chen PJ,Lin CL,Shih WL,Chen D S.Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men..J Natl Cancer Inst2005;97:265-72

[30] Kao JH,Lai MY.Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B..Gastroenterology2000;118:554-59

[31] Yin J,Li C,He Y,Zhang P,Tan X,Cheng S,Cao G.Role of hepatitis B virus genotype mixture, subgenotypes C2 and B2 on hepatocellular carcinoma: compared with chronic hepatitis B and asymptomatic carrier state in the same area..Carcinogenesis2008;29:1685-91

[32] Deng Y,Zhang Q,Cao G.Human cytidine deaminases facilitate hepatitis B virus evolution and link inflammation and hepatocellular carcinoma..Cancer Lett2014;343:161-71

[33] Liu S,Yin J,Zhang Q,Li C,Wang H.A matched case-control study of hepatitis B virus mutations in the preS and core promoter regions associated independently with hepatocellular carcinoma..J Med Virol2011;83:45-53

[34] Xie JX,Yin JH,Pu R,Zhang HW,Cao GW.Association of novel mutations and haplotypes in the preS region of hepatitis B virus with hepatocellular carcinoma..Front Med China2010;4:419-29

[35] Yuen MF,Fong D Y,Wong D K,But D Y,Wong B C,Lai C L.Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B..J Hepatol2009;50:80-8

[36] Yin J,Pu R,Li Z,Ding Y,Liu W,Ji X,Yu M,Wang H,Ni W.Hepatitis B virus combo mutations improve the prediction and active prophylaxis of hepatocellular carcinoma: a clinic-based cohort study..Cancer Prev Res (Phila)2015;8:978-88

[37] Han YF,Ma LY,Chang WJ,Cao GW.Factors predicting occurrence and prognosis of hepatitis-B-virus-related hepatocellular carcinoma..World J Gastroenterol2011;17:4258-70

[38] Chew V,Teo M,Chan J,Loh M,Quek R,Lee KH,Toh HC.Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients..J Hepatol2010;52:370-9

[39] Gao Q,Fan J,Wang XY,Xu Y,Tang ZY.Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection..J Clin Oncol2007;25:2586-93

[40] Du Q,Cardinal J,Guo Z,Geller DA.Wnt/beta-catenin signaling regulates cytokine-induced human inducible nitric oxide synthase expression by inhibiting nuclear factor-kappaB activation in cancer cells..Cancer Res2009;69:3764-71

[41] Pan L,Zheng W,Yang X,Cai Y,Yao D.Abnormality of Wnt3a expression as novel specific biomarker for diagnosis and differentiation of hepatocellular carcinoma..Tumour Biol2016;37:5561-8

[42] Ding SL,Wang J,Chen XM.Integrative analysis of aberrant Wnt signaling in hepatitis B virus-related hepatocellular carcinoma..World J Gastroenterol2015;21:6317-28 PMCID:PMC4445110

[43] Fabregat I.Dysregulation of apoptosis in hepatocellular carcinoma cells..World J Gastroenterol2009;15:513-20

[44] He Y,Yin J,Tan X,Zhang Q,Zhao J,Cao G.IkappaBalpha gene promoter polymorphisms are associated with hepatocarcinogenesis in patients infected with hepatitis B virus genotype C..Carcinogenesis2009;30:1916-22

[45] Du Y,Pu R,Zhang Y.Association of miRNA-122-binding site polymorphism at the interleukin-1 alpha gene and its interaction with hepatitis B virus mutations with hepatocellular carcinoma risk..Front Med2014;8:217-26

[46] Han Y,Han X,Li W,Zhang Y,Xie J,Jiang S,Zhang H,Cao G.Association of a potential functional pre-miR-218 polymorphism and its interaction with hepatitis B virus mutations with hepatocellular carcinoma risk..Liver Int2014;34:728-36

[47] Ji X,Li B,Yin J,Zhang H.Impacts of human leukocyte antigen DQ genetic polymorphisms and their interactions with hepatitis B virus mutations on the risks of viral persistence, liver cirrhosis, and hepatocellular carcinoma..Infect Genet Evol2014;28:201-9

[48] Andrisani OM,Merle P.Gene signatures in hepatocellular carcinoma (HCC)..Semin Cancer Biol2011;21:4-9

[49] Lee JS,Libbrecht L,Kaposi-Novak P,Mikaelyan A,Demetris AJ,Nevens F,Thorgeirsson SS.A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells..Nat Med2006;12:410-6

[50] Budhu A,Ye QH,He P,Kammula US,Qin LX,Wang XW.Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment..Cancer Cell2006;10:99-111

[51] Kaposi-Novak P,Gomez-Quiroz L,Factor VM.Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype..J Clin Invest2006;116:1582-95 PMCID:PMC1462944

[52] Wang SM,Hui KM.Identification and validation of a novel gene signature associated with the recurrence of human hepatocellular carcinoma..Clin Cancer Res2007;13:6275-83

[53] Boyault S,de Reynies A,Rebouissou S,Herault A,Belghiti J,Bioulac-Sage P,Zucman-Rossi J.Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets..Hepatology2007;45:42-52

[54] Woo HG,Cheon JH,Lee JS,Kim W,Chung YJ,Yoon JH,Kim CY,Suh KS,Chu IS,Thorgeirsson SS.Gene expression-based recurrence prediction of hepatitis B virus-related human hepatocellular carcinoma..Clin Cancer Res2008;14:2056-64

[55] Hoshida Y,Kobayashi M,Chiang DY,Gupta S,Wrobel MJ,Reich M,Glickman JN,Hashimoto M,Daidone MG,Schwartz M,Salvesen HB,Mazzaferro V,Friedman SL,Llovet JM.Gene expression in fixed tissues and outcome in hepatocellular carcinoma..N Engl J Med2008;359:1995-2004

[56] Coulouarn C,Thorgeirsson SS.Transforming growth factor-beta gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer..Hepatology2008;47:2059-67 PMCID:PMC2762280

[57] Yoshioka S,Nagano H,Noda T,Kobayashi S,Takeda Y,Dono K,Monden M.Molecular prediction of early recurrence after resection of hepatocellular carcinoma..Eur J Cancer2009;45:881-9

[58] Woo HG,Yoon JH,Lee HS,Yi NJ,Lee KU,Thorgeirsson S S.Identification of a cholangiocarcinoma-like gene expression trait in hepatocellular carcinoma..Cancer Res2010;70:3034-41 PMCID:PMC3498758

[59] Roessler S,Budhu A,Ye QH,Thorgeirsson SS,Tang ZY,Wang XW.A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients..Cancer Res2010;70:10202-12 PMCID:PMC3064515

[60] Villanueva A,Battiston C,Sia D,Cornella H,Kobayashi M,Thung S N,Newell P,Fan JB,Mazzaferro V,Llovet JM.Combining clinical, pathology, and gene expression data to predict recurrence of hepatocellular carcinoma..Gastroenterology2011;140:1501-12 PMCID:PMC3081971

[61] Minguez B,Villanueva A,Cabellos L,Mandeli J,April C,Lachenmayer A,Roayaie S,Bruix J,Friedman S L.Gene-expression signature of vascular invasion in hepatocellular carcinoma..J Hepatol2011;55:1325-31

[62] Weng L,Zhou Q,Li J,Ling C.Identification of cyclin B1 and Sec62 as biomarkers for recurrence in patients with HBV-related hepatocellular carcinoma after surgical resection..Mol Cancer2012;11:39 PMCID:PMC3439291

[63] Kim SM,Chu IS,Kim SC,Park ES,Heo J,Kim DG,Park YN,Thorgeirsson SS.Sixty-five gene-based risk score classifier predicts overall survival in hepatocellular carcinoma..Hepatology2012;55:1443-52 PMCID:PMC4060518

[64] Kim BY,Lee JG,Park IC,Han CJ,Jeong S H,Yang SJ,Cho SJ,Cho MH,Choi DW.Integrated analysis of prognostic gene expression profiles from hepatitis B virus-positive hepatocellular carcinoma and adjacent liver tissue..Ann Surg Oncol2012;19 Suppl 3:S328-38

[65] Lim HY,Deng S,Jung SH,Xu J,Shi S,Choi YL.Prediction of disease-free survival in hepatocellular carcinoma by gene expression profiling..Ann Surg Oncol2013;20:3747-53

[66] Kim JH,Lee HS,Yoo JE,Jeong W,Park E S,Kim BH,Yeon JE,Chu IS,Wang XW,Luk JM,Heo J,Lee JS.Genomic predictors for recurrence patterns of hepatocellular carcinoma: model derivation and validation..PLoS Med2014;11:e1001770

[67] Guichard C,Imbeaud S,Pelletier L,Calderaro J,Letexier M,Clement B,Chevet E,Couchy G,Calvo F.Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma..Nat Genet2012;44:694-8 PMCID:PMC3819251

[68] Kan Z,Liu X,Barber TD,Gao H,Willard MD,Hauptschein R,Fernandez J,Zhang Q,Chen R,Lee NP,Lin Z,Yi K,Li L,Yang J,Ju J,Estrella H,Wei P,Wulur IH,Ehsani ME,Loboda A,Aggarwal A,Fan ST,Hardwick J,Dai H,Luk JM.Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma..Genome Res2013;23:1422-33 PMCID:PMC3759719

[69] Ahn SM,Shim JH,Hong SM,Baek D,Ansari AA,Chun SM,Choi HJ,Kim S,Lee YJ,Jung WR,Yang E,Lee NP,Lee C,Yu E,Kong G.Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification..Hepatology2014;60:1972-82

[70] Schulze K,Letouze E,Calderaro J,Couchy G,Shinde J,Calatayud AL,Pelletier L,Laurent A,Mazzaferro V,Villanueva A,Bioulac-Sage P,Llovet JM.Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets..Nat Genet2015;47:505-11

[71] Totoki Y,Covington KR,Creighton CJ,Tsuji S,Slagle BL,Yamamoto S,Hama N,Hosoda F,Walker K,Gotoh K,Gingras MC,Ojima H,Midorikawa Y,Cotton R,Shibahara J,Guiteau J,Urushidate T,Okada N,Wang M,Dinh H,Kokudo N,Takayama T,Gibbs RA,Aburatani H.Trans-ancestry mutational landscape of hepatocellular carcinoma genomes..Nat Genet2014;46:1267-73

[72] Chaffer CL.A perspective on cancer cell metastasis..Science2011;331:1559-64

[73] Wu LJ,Pei XY,Nguyen S,Liu J.Capturing circulating tumor cells of hepatocellular carcinoma..Cancer Lett2012;326:17-22

[74] Sun Y F,Yang XR,Zhang X,Shi RY,Zhou J.Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection..Hepatology2013;57:1458-68

[75] Schulze K,Staufer K,Lohse AW,Riethdorf S.Presence of EpCAM-positive circulating tumor cells as biomarker for systemic disease strongly correlates to survival in patients with hepatocellular carcinoma..Int J Cancer2013;133:2165-71

[76] Tang JC,Guo T,Cai XJ.Circulating tumor DNA in hepatocellular carcinoma: trends and challenges..Cell Biosci2016;6:32 PMCID:PMC4866298

[77] Schwarzenbach H,Pantel K.Cell-free nucleic acids as biomarkers in cancer patients..Nat Rev Cancer2011;11:426-37

[78] Chan KC,Mok TS,Ding C,Lo YM.Quantitative analysis of circulating methylated DNA as a biomarker for hepatocellular carcinoma..Clin Chem2008;54:1528-36

[79] Wen L,Guo H,Zheng S,Zhu W,Guo L,Jin X,Gao Y,Ge H,Huang Y.Genome-scale detection of hypermethylated CpG islands in circulating cell-free DNA of hepatocellular carcinoma patients..Cell Res2015;25:1376

[80] Villar S,Gouas D A,Ferro G,Lereau M,Hall AJ,Mendy M,van der Sande M,Friesen MD,Hainaut P.Seasonal variation in TP53 R249S-mutated serum DNA with aflatoxin exposure and hepatitis B virus infection..Environ Health Perspect2011;119:1635-40

[81] Szymanska K,Cui Y,Turner P C,Wild C P,Hainaut P.TP53 R249S mutations, exposure to aflatoxin, and occurrence of hepatocellular carcinoma in a cohort of chronic hepatitis B virus carriers from Qidong, China..Cancer Epidemiol Biomarkers Prev2009;18:1638-43

[82] Hosny G,Tayel H.Ser-249 TP53 and CTNNB1 mutations in circulating free DNA of Egyptian patients with hepatocellular carcinoma versus chronic liver diseases..Cancer Lett2008;264:201-8