Strategies for hepatocellular carcinoma therapy and diagnostics: Lessons learned from high throughput and profiling approaches

Hepatology

Volumn 53, Issue 6, 2011, Pages 2112-2121

  Breuhahn, Kai ^a   Gores, Gregory ^b   Schirmacher, Peter ^a  

^a UNIVERSITY HOSPITAL HEIDELBERG   (Germany)

^b Mayo Clinic   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

MICRORNA; UNTRANSLATED RNA;

COMPARATIVE GENOMIC HYBRIDIZATION; CPG ISLAND; DNA METHYLATION; GENE MUTATION; GENOMIC INSTABILITY; HIGH THROUGHPUT SEQUENCING; HUMAN; LIVER CELL CARCINOMA; ONCOGENE; PRIORITY JOURNAL; PROTEIN ANALYSIS; REVIEW; TRANSCRIPTOMICS;

CARCINOMA, HEPATOCELLULAR; EPIGENOMICS; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION, NEOPLASTIC; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; LIVER NEOPLASMS; PROTEOMICS;

EID: 79957494402     PISSN: 02709139     EISSN: 15273350     Source Type: Journal    
DOI: 10.1002/hep.24313     Document Type: Review

References (109)

1. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. HEPATOLOGY 2011; 53: 1020-1022.
2. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. HEPATOLOGY 2009; 49: 658-664.
3. Newell P, Villanueva A, Friedman SL, Koike K, Llovet JM. Experimental models of hepatocellular carcinoma. J Hepatol 2008; 48: 858-879.
4. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132: 2557-2576.
5. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-390.
6. Salem R, Lewandowski RJ, Kulik L, Wang E, Riaz A, Ryu RK, et al. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology 2011; 140: 497-507.
7. Chang JF, Chen PJ, Sze DY, Reid T, Bartlett D, Kirn DH, et al. Oncolytic virotherapy for advanced liver tumours. J Cell Mol Med 2009; 13: 1238-1247.
8. Iizuka N, Oka M, Yamada-Okabe H, Mori N, Tamesa T, Okada T, et al. Comparison of gene expression profiles between hepatitis B virus- and hepatitis C virus-infected hepatocellular carcinoma by oligonucleotide microarray data on the basis of a supervised learning method. Cancer Res 2002; 62: 3939-3944.
9. Schlaeger C, Longerich T, Schiller C, Bewerunge P, Mehrabi A, Toedt G, et al. Etiology-dependent molecular mechanisms in human hepatocarcinogenesis. HEPATOLOGY 2008; 47: 511-520.
10. Takemoto N, Iizuka N, Yamada-Okabe H, Hamada K, Tamesa T, Okada T, et al. Sex-based molecular profiling of hepatitis C virus-related hepatocellular carcinoma. Int J Oncol 2005; 26: 673-678.
11. Kurokawa Y, Matoba R, Takemasa I, Nagano H, Dono K, Nakamori S, et al. Molecular-based prediction of early recurrence in hepatocellular carcinoma. J Hepatol 2004; 41: 284-291.
12. Iizuka N, Oka M, Yamada-Okabe H, Nishida M, Maeda Y, Mori N, et al. Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet 2003; 361: 923-929.
13. Kurokawa Y, Matoba R, Nagano H, Sakon M, Takemasa I, Nakamori S, et al. Molecular prediction of response to 5-fluorouracil and interferon-alpha combination chemotherapy in advanced hepatocellular carcinoma. Clin Cancer Res 2004; 10: 6029-6038.
14. 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: 410-416.
15. Moinzadeh P, Breuhahn K, Stutzer H, Schirmacher P. Chromosome alterations in human hepatocellular carcinomas correlate with aetiology and histological grade-results of an explorative CGH meta-analysis. Br J Cancer 2005; 92: 935-941.
16. Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res 2009; 69: 7385-7392.
17. Hudson TJ, Anderson W, Artez A, Barker AD, Bell C, Bernabe RR, et al. International network of cancer genome projects. Nature 2010; 464: 993-998.
18. Poon TC, Wong N, Lai PB, Rattray M, Johnson PJ, Sung JJ. A tumor progression model for hepatocellular carcinoma: bioinformatic analysis of genomic data. Gastroenterology 2006; 131: 1262-1270.
19. Kim TM, Yim SH, Shin SH, Xu HD, Jung YC, Park CK, et al. Clinical implication of recurrent copy number alterations in hepatocellular carcinoma and putative oncogenes in recurrent gains on 1q. Int J Cancer 2008; 123: 2808-2815.
20. Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J, et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 2006; 125: 1253-1267.
21. Patil MA, Gutgemann I, Zhang J, Ho C, Cheung ST, Ginzinger D, et al. Array-based comparative genomic hybridization reveals recurrent chromosomal aberrations and Jab1 as a potential target for 8q gain in hepatocellular carcinoma. Carcinogenesis 2005; 26: 2050-2057.
22. Soussi T, Lozano G. p53 mutation heterogeneity in cancer. Biochem Biophys Res Commun 2005; 331: 834-842.
23. Taniguchi K, Roberts LR, Aderca IN, Dong X, Qian C, Murphy LM, et al. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene 2002; 21: 4863-4871.
24. Prange W, Breuhahn K, Fischer F, Zilkens C, Pietsch T, Petmecky K, et al. Beta-catenin accumulation in the progression of human hepatocarcinogenesis correlates with loss of E-cadherin and accumulation of p53, but not with expression of conventional WNT-1 target genes. J Pathol 2003; 201: 250-259.
25. De Souza AT, Hankins GR, Washington MK, Orton TC, Jirtle RL. M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity. Nat Genet 1995; 11: 447-449.
26. 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.
27. Weihrauch M, Benicke M, Lehnert G, Wittekind C, Wrbitzky R, Tannapfel A. Frequent k- ras -2 mutations and p16(INK4A)methylation in hepatocellular carcinomas in workers exposed to vinyl chloride. Br J Cancer 2001; 84: 982-989.
28. Liew CT, Li HM, Lo KW, Leow CK, Chan JY, Hin LY, et al. High frequency of p16INK4A gene alterations in hepatocellular carcinoma. Oncogene 1999; 18: 789-795.
29. Gaudet F, Hodgson JG, Eden A, Jackson-Grusby L, Dausman J, Gray JW, et al. Induction of tumors in mice by genomic hypomethylation. Science 2003; 300: 489-492.
30. Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee JS, et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 2006; 130: 1117-1128.
31. Lee S, Lee HJ, Kim JH, Lee HS, Jang JJ, Kang GH. Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol 2003; 163: 1371-1378.
32. Hernandez-Vargas H, Lambert MP, Le Calvez-Kelm F, Gouysse G, McKay-Chopin S, Tavtigian SV, et al. Hepatocellular carcinoma displays distinct DNA methylation signatures with potential as clinical predictors. PLoS One 2010; 5: e9749.
33. Calvisi DF, Ladu S, Gorden A, Farina M, Lee JS, Conner EA, et al. Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. J Clin Invest 2007; 117: 2713-2722.
34. Arai E, Ushijima S, Gotoh M, Ojima H, Kosuge T, Hosoda F, et al. Genome-wide DNA methylation profiles in liver tissue at the precancerous stage and in hepatocellular carcinoma. Int J Cancer 2009; 125: 2854-2862.
35. Breuhahn K, Vreden S, Haddad R, Beckebaum S, Stippel D, Flemming P, et al. Molecular profiling of human hepatocellular carcinoma defines mutually exclusive interferon regulation and insulin-like growth factor II overexpression. Cancer Res 2004; 64: 6058-6064.
36. Lee JS, Chu IS, Heo J, Calvisi DF, Sun Z, Roskams T, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. HEPATOLOGY 2004; 40: 667-676.
37. Midorikawa Y, Makuuchi M, Tang W, Aburatani H. Microarray-based analysis for hepatocellular carcinoma: from gene expression profiling to new challenges. World J Gastroenterol 2007; 13: 1487-1492.
38. Chen X, Cheung ST, So S, Fan ST, Barry C, Higgins J, et al. Gene expression patterns in human liver cancers. Mol Biol Cell 2002; 13: 1929-1939.
39. Chiang DY, Villanueva A, Hoshida Y, Peix J, Newell P, Minguez B, et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res 2008; 68: 6779-6788.
40. Nam SW, Park JY, Ramasamy A, Shevade S, Islam A, Long PM, et al. Molecular changes from dysplastic nodule to hepatocellular carcinoma through gene expression profiling. HEPATOLOGY 2005; 42: 809-818.
41. Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, et al. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 2003; 9: 416-423.
42. Yu GR, Kim SH, Park SH, Cui XD, Xu DY, Yu HC, et al. Identification of molecular markers for the oncogenic differentiation of hepatocellular carcinoma. Exp Mol Med 2007; 39: 641-652.
43. Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 2009; 19: 92-105.
44. Place RF, Li LC, Pookot D, Noonan EJ, Dahiya R. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci U S A 2008; 105: 1608-1613.
45. Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci U S A 2007; 104: 15805-15810.
46. Pineau P, Volinia S, McJunkin K, Marchio A, Battiston C, Terris B, et al. miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci U S A 2010; 107: 264-269.
47. Wong QW, Lung RW, Law PT, Lai PB, Chan KY, To KF, et al. MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1. Gastroenterology 2008; 135: 257-269.
48. Ura S, Honda M, Yamashita T, Ueda T, Takatori H, Nishino R, et al. Differential microRNA expression between hepatitis B and hepatitis C leading disease progression to hepatocellular carcinoma. HEPATOLOGY 2009; 49: 1098-1112.
49. Ladeiro Y, Couchy G, Balabaud C, Bioulac-Sage P, Pelletier L, Rebouissou S, et al. MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. HEPATOLOGY 2008; 47: 1955-1963.
50. Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T, et al. Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene 2006; 25: 2537-2545.
51. Budhu A, Jia HL, Forgues M, Liu CG, Goldstein D, Lam A, et al. Identification of metastasis-related microRNAs in hepatocellular carcinoma. HEPATOLOGY 2008; 47: 897-907.
52. Jiang J, Gusev Y, Aderca I, Mettler TA, Nagorney DM, Brackett DJ, et al. Association of MicroRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival. Clin Cancer Res 2008; 14: 419-427.
53. Varnholt H, Drebber U, Schulze F, Wedemeyer I, Schirmacher P, Dienes HP, et al. MicroRNA gene expression profile of hepatitis C virus-associated hepatocellular carcinoma. HEPATOLOGY 2008; 47: 1223-1232.
54. Gramantieri L, Ferracin M, Fornari F, Veronese A, Sabbioni S, Liu CG, et al. Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res 2007; 67: 6092-6099.
55. Ji J, Shi J, Budhu A, Yu Z, Forgues M, Roessler S, et al. MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med 2009; 361: 1437-1447.
56. Wong CC, Wong CM, Tung EK, Au SL, Lee JM, Poon RT, et al. The microRNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating Rho-kinase 2. Gastroenterology 2011; 140: 322-331.
57. Liang L, Wong CM, Ying Q, Fan DN, Huang S, Ding J, et al. MicroRNA-125b suppressesed human liver cancer cell proliferation and metastasis by directly targeting oncogene LIN28B2. HEPATOLOGY 2010; 52: 1731-1740.
58. Ji J, Yamashita T, Budhu A, Forgues M, Jia HL, Li C, et al. Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells. HEPATOLOGY 2009; 50: 472-480.
59. Cairo S, Wang Y, de Reynies A, Duroure K, Dahan J, Redon MJ, et al. Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer. Proc Natl Acad Sci U S A 2010; 107: 20471-20476.
60. Cox B, Kislinger T, Emili A. Integrating gene and protein expression data: pattern analysis and profile mining. Methods 2005; 35: 303-314.
61. Rogers S, Girolami M, Kolch W, Waters KM, Liu T, Thrall B, et al. Investigating the correspondence between transcriptomic and proteomic expression profiles using coupled cluster models. Bioinformatics 2008; 24: 2894-2900.
62. Kim W, Oe Lim S, Kim JS, Ryu YH, Byeon JY, Kim HJ, et al. Comparison of proteome between hepatitis B virus- and hepatitis C virus-associated hepatocellular carcinoma. Clin Cancer Res 2003; 9: 5493-5500.
63. Sun Y, Zang Z, Xu X, Zhang Z, Zhong L, Zan W, et al. Differential proteomics identification of HSP90 as potential serum biomarker in hepatocellular carcinoma by two-dimensional electrophoresis and mass spectrometry. Int J Mol Sci 2010; 11: 1423-1433.
64. Li C, Tan YX, Zhou H, Ding SJ, Li SJ, Ma DJ, et al. Proteomic analysis of hepatitis B virus-associated hepatocellular carcinoma: identification of potential tumor markers. Proteomics 2005; 5: 1125-1139.
65. Bengochea A, de Souza MM, Lefrancois L, Le Roux E, Galy O, Chemin I, et al. Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma. Br J Cancer 2008; 99: 143-150.
66. Kiss A, Wang NJ, Xie JP, Thorgeirsson SS. Analysis of transforming growth factor (TGF)-alpha/epidermal growth factor receptor, hepatocyte growth factor/c-met, TGF-beta receptor type II, and p53 expression in human hepatocellular carcinomas. Clin Cancer Res 1997; 3: 1059-1066.
67. Cho S, Lee JH, Cho SB, Yoon KW, Park SY, Lee WS, et al. Epigenetic methylation and expression of caspase 8 and survivin in hepatocellular carcinoma. Pathol Int 2010; 60: 203-211.
68. Saegusa M, Takano Y, Kishimoto H, Wakabayashi G, Nohga K, Okudaira M. Comparative analysis of p53 and c-myc expression and cell proliferation in human hepatocellular carcinomas-an enhanced immunohistochemical approach. J Cancer Res Clin Oncol 1993; 119: 737-744.
69. Malz M, Weber A, Singer S, Riehmer V, Bissinger M, Riener MO, et al. Overexpression of far upstream element binding proteins: a mechanism regulating proliferation and migration in liver cancer cells. HEPATOLOGY 2009; 50: 1130-1139.
70. Xu MZ, Yao TJ, Lee NP, Ng IO, Chan YT, Zender L, et al. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer 2009; 115: 4576-4585.
71. Longerich T, Breuhahn K, Odenthal M, Petmecky K, Schirmacher P. Factors of transforming growth factor beta signalling are co-regulated in human hepatocellular carcinoma. Virchows Arch 2004; 445: 589-596.
72. Park YN, Chae KJ, Oh BK, Choi J, Choi KS, Park C. Expression of Smad7 in hepatocellular carcinoma and dysplastic nodules: resistance mechanism to transforming growth factor-beta. Hepatogastroenterology 2004; 51: 396-400.
73. Breuhahn K, Schirmacher P. Signaling networks in human hepatocarcinogenesis-novel aspects and therapeutic options. Prog Mol Biol Transl Sci 2010; 97: 251-277.
74. Breuhahn K, Longerich T, Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 2006; 25: 3787-3800.
75. Laurent-Puig P, Legoix P, Bluteau O, Belghiti J, Franco D, Binot F, et al. Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology 2001; 120: 1763-1773.
76. Katoh H, Ojima H, Kokubu A, Saito S, Kondo T, Kosuge T, et al. Genetically distinct and clinically relevant classification of hepatocellular carcinoma: putative therapeutic targets. Gastroenterology 2007; 133: 1475-1486.
77. Woo HG, Park ES, Lee JS, Lee YH, Ishikawa T, Kim YJ, et al. Identification of potential driver genes in human liver carcinoma by genomewide screening. Cancer Res 2009; 69: 4059-4066.
78. Lee JM, Wong CM, Ng IO. Hepatitis B virus-associated multistep hepatocarcinogenesis: a stepwise increase in allelic alterations. Cancer Res 2008; 68: 5988-5996.
79. Farazi PA, Glickman J, Horner J, Depinho RA. Cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression. Cancer Res 2006; 66: 4766-4773.
80. Lechel A, Holstege H, Begus Y, Schienke A, Kamino K, Lehmann U, et al. Telomerase deletion limits progression of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease. Gastroenterology 2007; 132: 1465-1475.
81. 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: 429-431.
82. Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet 2000; 24: 245-250.
83. Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, et al. The genomic landscapes of human breast and colorectal cancers. Science 2007; 318: 1108-1113.
84. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321: 1801-1806.
85. Liu LX, Lee NP, Chan VW, Xue W, Zender L, Zhang C, et al. Targeting cadherin-17 inactivates Wnt signaling and inhibits tumor growth in liver carcinoma. HEPATOLOGY 2009; 50: 1453-1463.
86. Nussbaum T, Samarin J, Ehemann V, Bissinger M, Ryschich E, Khamidjanov A, et al. Autocrine insulin-like growth factor-II stimulation of tumor cell migration is a progression step in human hepatocarcinogenesis. HEPATOLOGY 2008; 48: 146-156.
87. Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 2008; 135: 1972-1983.
88. Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008; 100: 698-711.
89. Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther 2009; 86: 97-100.
90. Mehta C, Gao P, Bhatt DL, Harrington RA, Skerjanec S, Ware JH. Optimizing trial design: sequential, adaptive, and enrichment strategies. Circulation 2009; 119: 597-605.
91. Breinig M, Caldas-Lopes E, Goeppert B, Malz M, Rieker R, Bergmann F, et al. Targeting heat shock protein 90 with non-quinone inhibitors: a novel chemotherapeutic approach in human hepatocellular carcinoma. HEPATOLOGY 2009; 50: 102-112.
92. Eikesdal HP, Kalluri R. Drug resistance associated with antiangiogenesis therapy. Semin Cancer Biol 2009; 19: 310-317.
93. Boominathan L. The tumor suppressors p53, p63, and p73 are regulators of microRNA processing complex. PLoS One 2010; 5: e10615.
94. Su X, Chakravarti D, Cho MS, Liu L, Gi YJ, Lin YL, et al. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature 2010; 467: 986-990.
95. Torres EM, Dephoure N, Panneerselvam A, Tucker CM, Whittaker CA, Gygi SP, et al. Identification of aneuploidy-tolerating mutations. Cell 2010; 143: 71-83.
96. Petersen J, Dandri M, Mier W, Lutgehetmann M, Volz T, von Weizsacker F, et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat Biotechnol 2008; 26: 335-341.
97. Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 2010; 28: 3219-3226.
98. Chen S, Zhang J, Wang R, Luo X, Chen H. The platinum-based treatments for advanced non-small cell lung cancer, is low/negative ERCC1 expression better than high/positive ERCC1 expression? A meta-analysis. Lung Cancer 2010; 70: 63-70.
99. Siegel AB, Olsen SK, Magun A, Brown RS Jr. Sorafenib: where do we go from here? HEPATOLOGY 2010; 52: 360-369.
100. Lasky T, Magder L. Hepatocellular carcinoma p53 G > T transversions at codon 249: the fingerprint of aflatoxin exposure? Environ Health Perspect 1997; 105: 392-397.
101. Kubicka S, Trautwein C, Schrem H, Tillmann H, Manns M. Low incidence of p53 mutations in European hepatocellular carcinomas with heterogeneous mutation as a rare event. J Hepatol 1995; 23: 412-419.
102. Wong CM, Ng IO. Molecular pathogenesis of hepatocellular carcinoma. Liver Int 2008; 28: 160-174.
103. Yamada T, De Souza AT, Finkelstein S, Jirtle RL. Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis. Proc Natl Acad Sci U S A 1997; 94: 10351-10355.
104. Oka Y, Waterland RA, Killian JK, Nolan CM, Jang HS, Tohara K, et al. M6P/IGF2R tumor suppressor gene mutated in hepatocellular carcinomas in Japan. HEPATOLOGY 2002; 35: 1153-1163.
105. Yakicier MC, Irmak MB, Romano A, Kew M, Ozturk M. Smad2 and Smad4 gene mutations in hepatocellular carcinoma. Oncogene 1999; 18: 4879-4883.
106. Zhang X, Xu HJ, Murakami Y, Sachse R, Yashima K, Hirohashi S, et al. Deletions of chromosome 13q, mutations in Retinoblastoma 1, and retinoblastoma protein state in human hepatocellular carcinoma. Cancer Res 1994; 54: 4177-4182.
107. Yao YJ, Ping XL, Zhang H, Chen FF, Lee PK, Ahsan H, et al. PTEN/MMAC1 mutations in hepatocellular carcinomas. Oncogene 1999; 18: 3181-3185.
108. Wang L, Wang WL, Zhang Y, Guo SP, Zhang J, Li QL. Epigenetic and genetic alterations of PTEN in hepatocellular carcinoma. Hepatol Res 2007; 37: 389-396.
109. Yeh KT, Chang JG, Chen YJ, Chen ST, Yu SY, Shih MC, et al. Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in hepatocellular carcinoma. Cancer Invest 2000; 18: 123-129.