Pathogenesis of hepatocellular carcinoma according to aetiology

Best Practice and Research: Clinical Gastroenterology

Volumn 28, Issue 5, 2014, Pages 937-947

  Nault, Jean Charles ^a,b,c,d  

^a INSERM   (France)

^b UNIVERSITÉ PARIS DESCARTES   (France)

^c HÔPITAL JEAN VERDIER   (France)

^d UNIVERSITÉ PARIS 13   (France)

Author keywords

[No Author keywords available]

Indexed keywords

AFLATOXIN B1; HEPATITIS B VIRUS X PROTEIN; PROTEIN P53; TP53 PROTEIN, HUMAN;

ALCOHOL CONSUMPTION; ALCOHOL LIVER DISEASE; AUTOIMMUNE HEPATITIS; CANCER CLASSIFICATION; CANCER PROGNOSIS; CANCER RISK; CHROMOSOMAL INSTABILITY; CHRONIC INFLAMMATION; FATTY LIVER; HEPATITIS B; HEPATITIS C; HUMAN; INSULIN RESISTANCE; LIVER CARCINOGENESIS; LIVER CELL; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; MALIGNANT TRANSFORMATION; METABOLIC SYNDROME X; MUTAGENESIS; NEXT GENERATION SEQUENCING; NONALCOHOLIC FATTY LIVER; NONHUMAN; OXIDATIVE STRESS; POINT MUTATION; PRIMARY BILIARY CIRRHOSIS; RARE DISEASE; REVIEW; STELLATE CELL; TELOMERE SHORTENING; TUMOR SUPPRESSOR GENE; WILSON DISEASE; CARCINOMA, HEPATOCELLULAR; COMPLICATION; GENE EXPRESSION REGULATION; GENETICS; LIVER NEOPLASMS; RISK FACTOR;

AFLATOXIN B1; CARCINOMA, HEPATOCELLULAR; HEPATITIS B; HEPATITIS C; HUMANS; LIVER CIRRHOSIS; LIVER NEOPLASMS; MUTAGENESIS, INSERTIONAL; POINT MUTATION; RISK FACTORS; TUMOR SUPPRESSOR PROTEIN P53;

EID: 84920385208     PISSN: 15216918     EISSN: 15321916     Source Type: Journal    
DOI: 10.1016/j.bpg.2014.08.006     Document Type: Review

References (110)

1. El-Serag HB. Hepatocellular carcinoma. N Engl J Med 2011; 365: 1118-27.
2. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379: 1245-55.
3. EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol 2012; 56: 908-43.
4. Bruix J, Sherman M. Management of hepatocellular carcinoma: An update. Hepatology 2011; 53: 1020-2.
5. Omata M, Lesmana LA, Tateishi R, Chen PJ, Lin SM, Yoshida H, et al. Asian Pacific association for the study of the liver consensus recommendations on hepatocellular carcinoma. Hepatol Int 2010; 4: 439-74.
6. Moeini A, Cornella H, Villanueva A. Emerging signaling pathways in hepatocellular carcinoma. Liver Cancer 2012; 1: 83-93.
7. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: From genes to environment. Nat Rev Cancer 2006; 6: 674-87.
8. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz Jr. LA, Kinzler KW. Cancer genome landscapes. Science 2013; 339: 1546-58.
9. Nault JC, Zucman-Rossi J. Genetics of hepatobiliary carcinogenesis. Semin Liver Dis 2011; 31: 173-87.
10. Stratton MR. Exploring the genomes of cancer cells: Progress and promise. Science 2011; 331: 1553-8.
11. Neuveut C, Wei Y, Buendia MA. Mechanisms of HBV-related hepatocarcinogenesis. J Hepatol 2010; 52: 594-604.
12. Galibert F, Mandart E, Fitoussi F, Tiollais P, Charnay P. Nucleotide sequence of the hepatitis B virus genome (subtype ayw) cloned in E. coli. Nature 1979; 281: 646-50.
13. Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D, Abbruzzese JL, et al. Risk factors for hepatocellular carcinoma: Synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology 2002; 36: 1206-13.
14. Sun CA, Wu DM, Lin CC, Lu SN, You SL, Wang LY, et al. Incidence and cofactors of hepatitis C virus-related hepatocellular carcinoma: A prospective study of 12,008 men in Taiwan. Am J Epidemiol 2003; 157: 674-82.
15. Brechot C, Pourcel C, Louise A, Rain B, Tiollais P. Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma. Nature 1980; 286: 533-5.
16. Dejean A, Bougueleret L, Grzeschik KH, Tiollais P. Hepatitis B virus DNA integration in a sequence homologous to v-erb-A and steroid receptor genes in a hepatocellular carcinoma. Nature 1986; 322: 70-2.
17. Sung WK, Zheng H, Li S, Chen R, Liu X, Li Y, et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet 2012; 44: 765-9.
18. Brechot C. Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: Old and new paradigms. Gastroenterology 2004; 127: S56-61.
19. Li X, Zhang J, Yang Z, Kang J, Jiang S, Zhang T, et al. The function of targeted host genes determines the oncogenicity of HBV integration in hepatocellular carcinoma. J Hepatol 2014; 60: 975-84.
20. Paterlini-Brechot P, Saigo K, Murakami Y, Chami M, Gozuacik D, Mugnier C, et al. Hepatitis B virus-related insertional mutagenesis occurs frequently in human liver cancers and recurrently targets human telomerase gene. Oncogene 2003; 22: 3911-6.
21. Hino O, Tabata S, Hotta Y. Evidence for increased in vitro recombination with insertion of human hepatitis B virus DNA. Proc Natl Acad Sci U S A 1991; 88: 9248-52.
22. Tokino T, Fukushige S, Nakamura T, Nagaya T, Murotsu T, Shiga K, et al. Chromosomal translocation and inverted duplication associated with integrated hepatitis B virus in hepatocellular carcinomas. J Virol 1987; 61: 3848-54.
23. Bouchard MJ, Schneider RJ. The enigmatic X gene of hepatitis B virus. J Virol 2004; 78: 12725-34.
24. Andrisani OM, Barnabas S. The transcriptional function of the hepatitis B virus X protein and its role in hepatocarcinogenesis (review) . Int J Oncol 1999; 15: 373-9.
25. Benhenda S, Cougot D, Buendia MA, Neuveut C. Hepatitis B virus X protein molecular functions and its role in virus life cycle and pathogenesis. Adv Cancer Res 2009; 103: 75-109.
26. Chung TW, Lee YC, Kim CH. Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: Involvement of invasive potential. FASEB J 2004; 18: 1123-5.
27. Cougot D, Wu Y, Cairo S, Caramel J, Renard CA, Levy L, et al. The hepatitis B virus X protein functionally interacts with CREB-binding protein/p300 in the regulation of CREB-mediated transcription. J Biol Chem 2007; 282: 4277-87.
28. Seifer M, Hohne M, Schaefer S, Gerlich WH. In vitro tumorigenicity of hepatitis B virus DNA and HBx protein. J Hepatol 1991; 13 (Suppl. 4) : S61-5.
29. Kim YC, Song KS, Yoon G, Nam MJ, Ryu WS. Activated ras oncogene collaborates with HBx gene of hepatitis B virus to transform cells by suppressing HBx-mediated apoptosis. Oncogene 2001; 20: 16-23.
30. Oishi N, Shilagardi K, Nakamoto Y, Honda M, Kaneko S, Murakami S. Hepatitis B virus X protein overcomes oncogenic RAS-induced senescence in human immortalized cells. Cancer Sci 2007; 98: 1540-8.
31. Schuster R, Gerlich WH, Schaefer S. Induction of apoptosis by the transactivating domains of the hepatitis B virus X gene leads to suppression of oncogenic transformation of primary rat embryo fibroblasts. Oncogene 2000; 19: 1173-80.
32. Kim CM, Koike K, Saito I, Miyamura T, Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 1991; 351: 317-20.
33. Reifenberg K, Lohler J, Pudollek HP, Schmitteckert E, Spindler G, Kock J, et al. Long-term expression of the hepatitis B virus core-e-and X-proteins does not cause pathologic changes in transgenic mice. J Hepatol 1997; 26: 119-30.
34. Amaddeo GCQ, Ladeiro Y, Imbeaud S, Nault JC, Jaoui D, Mathe YG, et al. Integration of tumour and viral genomic characterisations in HBV-related hepatocellular carcinomas. Published Online First: 9 June 2014 Gut 2014. http://dx.doi.org/10.1136/gutjnl-2013-306228.
35. Wen Y, Golubkov VS, Strongin AY, Jiang W, Reed JC. Interaction of hepatitis B viral oncoprotein with cellular target HBXIP dysregulates centrosome dynamics and mitotic spindle formation. J Biol Chem 2008; 283: 2793-803.
36. Kim S, Park SY, Yong H, Famulski JK, Chae S, Lee JH, et al. HBV X protein targets hBubR1, which induces dysregulation of the mitotic checkpoint. Oncogene 2008; 27: 3457-64.
37. Liang TJ, Ghany MG. Current and future therapies for hepatitis C virus infection. N Engl J Med 2013; 368: 1907-17.
38. Bartosch B, Thimme R, Blum HE, Zoulim F. Hepatitis C virus-induced hepatocarcinogenesis. J Hepatol 2009; 51: 810-20.
39. Marcellin P, Asselah T, Boyer N. Fibrosis and disease progression in hepatitis C. Hepatology 2002; 36: S47-56.
40. Shimoda R, Nagashima M, Sakamoto M, Yamaguchi N, Hirohashi S, Yokota J, et al. Increased formation of oxidative DNA damage, 8-hydroxydeoxyguanosine, in human livers with chronic hepatitis. Cancer Res 1994; 54: 3171-2.
41. Lerat H, Honda M, Beard MR, Loesch K, Sun J, Yang Y, et al. Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. Gastroenterology 2002; 122: 352-65.
42. Moriya K, Nakagawa K, Santa T, Shintani Y, Fujie H, Miyoshi H, et al. Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res 2001; 61: 4365-70.
43. Leandro G, Mangia A, Hui J, Fabris P, Rubbia-Brandt L, Colloredo G, et al. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: A meta-analysis of individual patient data. Gastroenterology 2006; 130: 1636-42.
44. Grobholz R, Hacker HJ, Thorens B, Bannasch P. Reduction in the expression of glucose transporter protein GLUT 2 in preneoplastic and neoplastic hepatic lesions and reexpression of GLUT 1 in late stages of hepatocarcinogenesis. Cancer Res 1993; 53: 4204-11.
45. Negro F. Mechanisms of hepatitis C virus-related insulin resistance. Clin Res Hepatol Gastroenterol 2011; 35: 358-63.
46. Negro F. Mechanisms and significance of liver steatosis in hepatitis C virus infection. World J Gastroenterol 2006; 12: 6756-65.
47. Kumar D, Farrell GC, Fung C, George J. Hepatitis C virus genotype 3 is cytopathic to hepatocytes: Reversal of hepatic steatosis after sustained therapeutic response. Hepatology 2002; 36: 1266-72.
48. Ray RB, Steele R, Meyer K, Ray R. Transcriptional repression of p53 promoter by hepatitis C virus core protein. J Biol Chem 1997; 272: 10983-6.
49. Joo M, Hahn YS, Kwon M, Sadikot RT, Blackwell TS, Christman JW. Hepatitis C virus core protein suppresses NF-kappaB activation and cyclooxygenase-2 expression by direct interaction with IkappaB kinase beta. J Virol 2005; 79: 7648-57.
50. Sakamuro D, Furukawa T, Takegami T. Hepatitis C virus nonstructural protein NS3 transforms NIH 3T3 cells. J Virol 1995; 69: 3893-6.
51. Moriya K, Fujie H, Shintani Y, Yotsuyanagi H, Tsutsumi T, Ishibashi K, et al. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med 1998; 4: 1065-7.
52. Seitz HK, Stickel F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 2007; 7: 599-612.
53. De Bac C, Stroffolini T, Gaeta GB, Taliani G, Giusti G. Pathogenic factors in cirrhosis with and without hepatocellular carcinoma: A multicenter Italian study. Hepatology 1994; 20: 1225-30.
54. Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology 2004; 127: S87-96.
55. Grando-Lemaire V, Guettier C, Chevret S, Beaugrand M, Trinchet JC. Hepatocellular carcinoma without cirrhosis in the West: Epidemiological factors and histopathology of the non-tumorous liver. Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire. J Hepatol 1999; 31: 508-13.
56. Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, et al. Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 1993; 328: 1797-801.
57. Farber E. Alcohol and other chemicals in the development of hepatocellular carcinoma. Clin Lab Med 1996; 16: 377-94.
58. Stickel F, Schuppan D, Hahn EG, Seitz HK. Cocarcinogenic effects of alcohol in hepatocarcinogenesis. Gut 2002; 51: 132-9.
59. Seitz HK, Simanowski UA, Garzon FT, Rideout JM, Peters TJ, Koch A, et al. Possible role of acetaldehyde in ethanol-related rectal cocarcinogenesis in the rat. Gastroenterology 1990; 98: 406-13.
60. Bradford BU, Kono H, Isayama F, Kosyk O, Wheeler MD, Akiyama TE, et al. Cytochrome P450 CYP2E1, but not nicotinamide adenine dinucleotide phosphate oxidase, is required for ethanol-induced oxidative DNA damage in rodent liver. Hepatology 2005; 41: 336-44.
61. Theruvathu JA, Jaruga P, Nath RG, Dizdaroglu M, Brooks PJ. Polyamines stimulate the formation of mutagenic 1,N2-propanodeoxyguanosine adducts from acetaldehyde. Nucleic Acids Res 2005; 33: 3513-20.
62. Nahon P, Sutton A, Rufat P, Ziol M, Akouche H, Laguillier C, et al. Myeloperoxidase and superoxide dismutase 2 polymorphisms comodulate the risk of hepatocellular carcinoma and death in alcoholic cirrhosis. Hepatology 2009; 50: 1484-93.
63. Nahon P, Sutton A, Rufat P, Ziol M, Thabut G, Schischmanoff PO, et al. Liver iron, HFE gene mutations, and hepatocellular carcinoma occurrence in patients with cirrhosis. Gastroenterology 2008; 134: 102-10.
64. Wang XD, Liu C, Chung J, Stickel F, Seitz HK, Russell RM. Chronic alcohol intake reduces retinoic acid concentration and enhances AP-1 (c-Jun and c-Fos) expression in rat liver. Hepatology 1998; 28: 744-50.
65. Lu SC, Alvarez L, Huang ZZ, Chen L, An W, Corrales FJ, et al. Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation. Proc Natl Acad Sci U S A 2001; 98: 5560-5.
66. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003; 348: 1625-38.
67. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126: 460-8.
68. N'Kontchou G, Paries J, Htar MT, Ganne-Carrie N, Costentin L, Grando-Lemaire V, et al. Risk factors for hepatocellular carcinoma in patients with alcoholic or viral C cirrhosis. Clin Gastroenterol Hepatol 2006; 4: 1062-8.
69. Paradis V, Zalinski S, Chelbi E, Guedj N, Degos F, Vilgrain V, et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: A pathological analysis. Hepatology 2009; 49: 851-9.
70. Ertle J, Dechene A, Sowa JP, Penndorf V, Herzer K, Kaiser G, et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer 2011; 128: 2436-43.
71. Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: An emerging menace. J Hepatol 2012; 56: 1384-91.
72. Siddique A, Kowdley KV. Insulin resistance and other metabolic risk factors in the pathogenesis of hepatocellular carcinoma. Clin Liver Dis 2011; 15: 281-96 [viiex].
73. Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010; 140: 197-208.
74. Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 2012; 21: 504-16.
75. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013; 499: 97-101.
76. Kamada Y, Matsumoto H, Tamura S, Fukushima J, Kiso S, Fukui K, et al. Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model. J Hepatol 2007; 47: 556-64.
77. Ramani K, Yang H, Xia M, Ara AI, Mato JM, Lu SC. Leptin's mitogenic effect in human liver cancer cells requires induction of both methionine adenosyltransferase 2A and 2beta. Hepatology 2008; 47: 521-31.
78. Yamashita T, Honda M, Takatori H, Nishino R, Minato H, Takamura H, et al. Activation of lipogenic pathway correlates with cell proliferation and poor prognosis in hepatocellular carcinoma. J Hepatol 2009; 50: 100-10.
79. Gallagher EJ, LeRoith D. Minireview: IGF, insulin, and cancer. Endocrinology 2011; 152: 2546-51.
80. Tovar V, Alsinet C, Villanueva A, Hoshida Y, Chiang DY, Sole M, et al. IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. J Hepatol 2010; 52: 550-9.
81. Kew MC. Hepatic iron overload and hepatocellular carcinoma. Liver Cancer 2014; 3: 31-40.
82. Deugnier YM, Charalambous P, Le Quilleuc D, Turlin B, Searle J, Brissot P, et al. Preneoplastic significance of hepatic ironfree foci in genetic hemochromatosis: A study of 185 patients. Hepatology 1993; 18: 1363-9.
83. Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet 2012; 44: 694-8.
84. Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH, et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet 2012; 44: 760-4.
85. Huang J, Deng Q, Wang Q, Li KY, Dai JH, Li N, et al. Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma. Nat Genet 2012; 44: 1117-21.
86. Ahn SM, Jang SJ, Shim JH, Kim D, Hong SM, Sung CO, et al. A genomic portrait of resectable hepatocellular carcinomas: Implications of RB1 and FGF19 aberrations for patient stratification. Hepatology 2014.
87. Kan Z, Zheng H, Liu X, Li S, Barber T, Gong Z, et al. Whole genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res 2013.
88. Cleary SP, Jeck WR, Zhao X, Kuichen, Selitsky SR, Savich GL, et al. Identification of driver genes in hepatocellular carcinoma by exome sequencing. Hepatology 2013 Nov; 58 (5) : 1693-702.
89. de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, et al. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci U S A 1998 Jul 21; 95 (15) : 8847-51.
90. Bressac B, Kew M, Wands J, Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 1991; 350: 429-31.
91. Woo HG, Wang XW, Budhu A, Kim YH, Kwon SM, Tang ZY, et al. Association of TP53 mutations with stem cell-like gene expression and survival of patients with hepatocellular carcinoma. Gastroenterology 2011; 140: 1063-70.
92. Hussain SP, Schwank J, Staib F, Wang XW, Harris CC. TP53 mutations and hepatocellular carcinoma: Insights into the etiology and pathogenesis of liver cancer. Oncogene 2007; 26: 2166-76.
93. Gouas D, Shi H, Hainaut P. The aflatoxin-induced TP53 mutation at codon 249 (R249S) : Biomarker of exposure, early detection and target for therapy. Cancer Lett 2009; 286: 29-37.
94. Poon SL, Pang ST, McPherson JR, Yu W, Huang KK, Guan P, et al. Genome-wide mutational signatures of aristolochic acid and its application as a screening tool. Sci Transl Med 2013; 5: 197ra01.
95. Alexandrov LB, Stratton MR. Mutational signatures: The patterns of somatic mutations hidden in cancer genomes. Curr Opin Genet Dev 2014; 24: 52-60.
96. Farazi PA, Glickman J, Jiang S, Yu A, Rudolph KL, DePinho RA. Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma. Cancer Res 2003; 63: 5021-7.
97. Nault JC, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, Laurent C, et al. High frequency of telomerase reversetranscriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun 2013; 4: 2218.
98. Chen YL, Jeng YM, Chang CN, Lee HJ, Hsu HC, Lai PL, et al. TERT promoter mutation in resectable hepatocellular carcinomas: A strong association with hepatitis C infection and absence of hepatitis B infection. Int J Surg 2014.
99. Sawey ET, Chanrion M, Cai C, Wu G, Zhang J, Zender L, et al. Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell 2011 Mar 8; 19 (3) : 347-58.
100. Paradis V, Albuquerque M, Mebarki M, Hernandez L, Zalinski S, Quentin S, et al. Cullin7: A new gene involved in liver carcinogenesis related to metabolic syndrome. Gut 2013; 62: 911-9.
101. Villanueva A, Hoshida Y, Battiston C, Tovar V, Sia D, Alsinet C, et al. Combining clinical, pathology, and gene expression data to predict recurrence of hepatocellular carcinoma. Gastroenterology 2011; 140. 1501-1512 e2.
102. Boyault S, Rickman DS, de Reynies A, Balabaud C, Rebouissou S, Jeannot E, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 2007; 45: 42-52.
103. Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 2006; 12: 410-6.
104. Chan AW, Tong JH, Chan SL, Lai PB, To KF. Expression of stemness markers (CD133 and EpCAM) in prognostication of hepatocellular carcinoma. Histopathology 2014; 64: 935-50.
105. Nault JC, De Reynies A, Villanueva A, Calderaro J, Rebouissou S, Couchy G, et al. A hepatocellular carcinoma 5-gene score associated with survival of patients after liver resection. Gastroenterology 2013; 145: 176-87.
106. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132: 2557-76.
107. Gunes C, Rudolph KL. The role of telomeres in stem cells and cancer. Cell 2013; 152: 390-3.
108. Nault JC, Bioulac-Sage P, Zucman-Rossi J. Hepatocellular benign tumors-from molecular classification to personalized clinical care. Gastroenterology 2013; 144: 888-902.
109. Pilati C, Letouze E, Nault JC, Imbeaud S, Boulai A, Calderaro J, et al. Genomic Profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation. Cancer Cell 2014; 25: 428-41.
110. Zucman-Rossi J, Jeannot E, Nhieu JT, Scoazec JY, Guettier C, Rebouissou S, et al. Genotype-phenotype correlation in hepatocellular adenoma: New classification and relationship with HCC. Hepatology 2006; 43: 515-24.