Molecular Profiling of Liver Tumors: Classification and Clinical Translation for Decision Making

 

 Buy Article Permissions and Reprints

Abstract

Hepatocellular carcinoma (HCC) is a complex disease with a dismal prognosis. Consequently, a translational approach is required to personalized clinical decision making to improve survival of HCC patients. Molecular signatures from cirrhotic livers and single nucleotide polymorphism have been linked with HCC occurrence. Identification of high-risk populations will be useful to design chemopreventive trials. In addition, molecular signatures derived from tumor and nontumor samples are associated with early tumor recurrence due to metastasis and late tumor recurrence due to de novo carcinogenesis after curative treatment, respectively. Identification of patients with a high risk of relapse will guide adjuvant randomized trials. The genetic landscape drawn by next-generation sequencing has highlighted the genomic diversity of HCC. Genetic drivers recurrently mutated belong to different signaling pathways including telomere maintenance, cell-cycle regulators, chromatin remodeling, Wnt/b-catenin, RAS/RAF/MAPK kinase, and AKT/mTOR pathway. These cancer genes will be ideally targeted by biotherapies as a paradigm of stratified medicine adapted to tumor biology.

• References

• 1 Lozano R, Naghavi M, Foreman K , et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380 (9859) 2095-2128
  CrossrefPubMedGoogle Scholar
• 2 Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin 2009; 59 (4) 225-249
  CrossrefPubMedGoogle Scholar
• 3 El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012; 142 (6) 1264-1273 , e1
  CrossrefPubMedGoogle Scholar
• 4 Bruix J, Sherman M. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005; 42 (5) 1208-1236
  CrossrefPubMedGoogle Scholar
• 5 Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003; 362 (9399) 1907-1917
  CrossrefPubMedGoogle Scholar
• 6 Llovet JM, Ricci S, Mazzaferro V , et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359 (4) 378-390
  CrossrefPubMedGoogle Scholar
• 7 El-Serag HB. Hepatocellular carcinoma. N Engl J Med 2011; 365 (12) 1118-1127
  CrossrefPubMedGoogle Scholar
• 8 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
• 9 Koike K. Hepatitis C virus contributes to hepatocarcinogenesis by modulating metabolic and intracellular signaling pathways. J Gastroenterol Hepatol 2007; 22 (Suppl. 01) S108-S111
  CrossrefPubMedGoogle Scholar
• 10 Bolondi L, Sofia S, Siringo S , et al. Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis. Gut 2001; 48 (2) 251-259
  CrossrefPubMedGoogle Scholar
• 11 Friedman SL. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 2010; 7 (8) 425-436
  CrossrefPubMedGoogle Scholar
• 12 Hoshida Y, Fuchs BC, Tanabe KK. Prevention of hepatocellular carcinoma: potential targets, experimental models, and clinical challenges. Curr Cancer Drug Targets 2012; 12 (9) 1129-1159
  PubMedGoogle Scholar
• 13 Wurmbach E, Chen YB, Khitrov G , et al. Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology 2007; 45 (4) 938-947
  CrossrefPubMedGoogle Scholar
• 14 Gehrau RC, Archer KJ, Mas VR, Maluf DG. Molecular profiles of HCV cirrhotic tissues derived in a panel of markers with clinical utility for hepatocellular carcinoma surveillance. PLoS ONE 2012; 7 (7) e40275
  CrossrefPubMedGoogle Scholar
• 15 Nam SW, Park JY, Ramasamy A , et al. Molecular changes from dysplastic nodule to hepatocellular carcinoma through gene expression profiling. Hepatology 2005; 42 (4) 809-818
  CrossrefPubMedGoogle Scholar
• 16 Budhu A, Forgues M, Ye Q-H , et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 2006; 10 (2) 99-111
  CrossrefPubMedGoogle Scholar
• 17 Hoshida Y, Villanueva A, Sangiovanni A , et al. Prognostic gene expression signature for patients with hepatitis C-related early-stage cirrhosis. Gastroenterology 2013; 144 (5) 1024-1030
  CrossrefPubMedGoogle Scholar
• 18 Kojima K, April C, Canasto-Chibuque C , et al. Transcriptome profiling of archived sectioned formalin-fixed paraffin-embedded (AS-FFPE) tissue for disease classification. PLoS ONE 2014; 9 (1) e86961
  CrossrefPubMedGoogle Scholar
• 19 Karlsen TH, Melum E, Franke A. The utility of genome-wide association studies in hepatology. Hepatology 2010; 51 (5) 1833-1842
  CrossrefPubMedGoogle Scholar
• 20 Stadler ZK, Gallagher DJ, Thom P, Offit K. Genome-wide association studies of cancer: principles and potential utility. Oncology (Williston Park) 2010; 24 (7) 629-637
  PubMedGoogle Scholar
• 21 Nahon P, Zucman-Rossi J. Single nucleotide polymorphisms and risk of hepatocellular carcinoma in cirrhosis. J Hepatol 2012; 57 (3) 663-674
  CrossrefPubMedGoogle Scholar
• 22 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 (1) 141-149
  CrossrefPubMedGoogle Scholar
• 23 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 (1) 53-60
  CrossrefPubMedGoogle Scholar
• 24 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 (5) 455-458
  CrossrefPubMedGoogle Scholar
• 25 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 (8) 797-800
  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 (9) 755-758
  CrossrefPubMedGoogle Scholar
• 27 Chan KY-K, Wong C-M, Kwan JS-H , et al. Genome-wide association study of hepatocellular carcinoma in southern Chinese patients with chronic hepatitis B virus infection. PLoS ONE 2011; 6 (12) e28798
  CrossrefPubMedGoogle Scholar
• 28 Jiang D-K, 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 (1) 72-75
  PubMedGoogle Scholar
• 29 European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56 (4) 908-943
  CrossrefPubMedGoogle Scholar
• 30 Bruix J, Sherman M. American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53 (3) 1020-1022
  CrossrefPubMedGoogle Scholar
• 31 Di Tommaso L, Sangiovanni A, Borzio M, Park YN, Farinati F, Roncalli M. Advanced precancerous lesions in the liver. Best Pract Res Clin Gastroenterol 2013; 27 (2) 269-284
  CrossrefPubMedGoogle Scholar
• 32 Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379 (9822) 1245-1255
  CrossrefPubMedGoogle Scholar
• 33 International Consensus Group for Hepatocellular Neoplasia: The International Consensus Group for Hepatocellular Neoplasia. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology 2009; 49 (2) 658-664
  CrossrefPubMedGoogle Scholar
• 34 Nault JC, Bioulac-Sage P, Zucman-Rossi J. Hepatocellular benign tumors-from molecular classification to personalized clinical care. Gastroenterology 2013; 144 (5) 888-902
  CrossrefPubMedGoogle Scholar
• 35 Finegold MJ, Geller SA, Gerber MA. International Working Party. Terminology of nodular hepatocellular lesions. Hepatology 1995; 22 (3) 983-993
  CrossrefPubMedGoogle Scholar
• 36 Di Tommaso L, Franchi G, Park YN , et al. Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis. Hepatology 2007; 45 (3) 725-734
  CrossrefPubMedGoogle Scholar
• 37 Tremosini S, Forner A, Boix L , et al. Prospective validation of an immunohistochemical panel (glypican 3, heat shock protein 70 and glutamine synthetase) in liver biopsies for diagnosis of very early hepatocellular carcinoma. Gut 2012; 61 (10) 1481-1487
  CrossrefPubMedGoogle Scholar
• 38 Di Tommaso L, Destro A, Fabbris V , et al. Diagnostic accuracy of clathrin heavy chain staining in a marker panel for the diagnosis of small hepatocellular carcinoma. Hepatology 2011; 53 (5) 1549-1557
  CrossrefPubMedGoogle Scholar
• 39 Paradis V, Bièche I, Dargère D , et al. Molecular profiling of hepatocellular carcinomas (HCC) using a large-scale real-time RT-PCR approach: determination of a molecular diagnostic index. Am J Pathol 2003; 163 (2) 733-741
  CrossrefPubMedGoogle Scholar
• 40 Llovet JM, Chen Y, Wurmbach E , et al. A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis. Gastroenterology 2006; 131 (6) 1758-1767
  CrossrefPubMedGoogle Scholar
• 41 Nault JC, Mallet M, Pilati C , et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun 2013; 4: 2218
  PubMedGoogle Scholar
• 42 Pinyol R, Tovar V, Llovet JM. TERT promoter mutations: gatekeeper and driver of hepatocellular carcinoma. J Hepatol 2014; 61 (3) 685-687
  CrossrefPubMedGoogle Scholar
• 43 Nault JC, Zucman-Rossi J. Genetics of hepatobiliary carcinogenesis. Semin Liver Dis 2011; 31 (2) 173-187
  Article in Thieme ConnectPubMedGoogle Scholar
• 44 Zucman-Rossi J, Jeannot E, Nhieu JT , et al. Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatology 2006; 43 (3) 515-524
  CrossrefPubMedGoogle Scholar
• 45 Van der Borght S, Libbrecht L, Katoonizadeh A , et al. Nuclear beta-catenin staining and absence of steatosis are indicators of hepatocellular adenomas with an increased risk of malignancy. Histopathology 2007; 51 (6) 855-856
  CrossrefPubMedGoogle Scholar
• 46 Pilati C, Letouzé E, Nault J-C , et al. Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation. Cancer Cell 2014; 25 (4) 428-441
  CrossrefPubMedGoogle Scholar
• 47 Villanueva A, Hoshida Y, Toffanin S , et al. New strategies in hepatocellular carcinoma: genomic prognostic markers. Clin Cancer Res 2010; 16 (19) 4688-4694
  CrossrefPubMedGoogle Scholar
• 48 Imamura H, Matsuyama Y, Tanaka E , et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003; 38 (2) 200-207
  PubMedGoogle Scholar
• 49 Villanueva A, Hoshida Y, Battiston C , et al. Combining clinical, pathology, and gene expression data to predict recurrence of hepatocellular carcinoma. Gastroenterology 2011; 140 (5) 1501-1512 , e2
  CrossrefPubMedGoogle Scholar
• 50 Nault JC, De Reyniès A, Villanueva A , et al. A hepatocellular carcinoma 5-gene score associated with survival of patients after liver resection. Gastroenterology 2013; 145 (1) 176-187
  CrossrefPubMedGoogle Scholar
• 51 Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009; 101 (21) 1446-1452
  CrossrefPubMedGoogle Scholar
• 52 McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics. REporting recommendations for tumour MARKer prognostic studies (REMARK). Eur J Cancer 2005; 41 (12) 1690-1696
  CrossrefPubMedGoogle Scholar
• 53 Hemingway H, Croft P, Perel P , et al; PROGRESS Group. Prognosis research strategy (PROGRESS) 1: a framework for researching clinical outcomes. BMJ 2013; 346: e5595
  CrossrefPubMedGoogle Scholar
• 54 Riley RD, Hayden JA, Steyerberg EW , et al; PROGRESS Group. Prognosis research strategy (PROGRESS) 2: prognostic factor research. PLoS Med 2013; 10 (2) e1001380
  CrossrefPubMedGoogle Scholar
• 55 Steyerberg EW, Moons KG, van der Windt DA , et al; PROGRESS Group. Prognosis research strategy (PROGRESS) 3: prognostic model research. PLoS Med 2013; 10 (2) e1001381
  CrossrefPubMedGoogle Scholar
• 56 Hingorani AD, Windt DA, Riley RD , et al; PROGRESS Group. Prognosis research strategy (PROGRESS) 4: stratified medicine research. BMJ 2013; 346: e5793
  CrossrefPubMedGoogle Scholar
• 57 Lee J-S, Chu I-S, Heo J , et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology 2004; 40 (3) 667-676
  CrossrefPubMedGoogle Scholar
• 58 Boyault S, Rickman DS, de Reyniès A , et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 2007; 45 (1) 42-52
  CrossrefPubMedGoogle Scholar
• 59 Coulouarn C, Factor VM, Thorgeirsson SS. Transforming growth factor-beta gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer. Hepatology 2008; 47 (6) 2059-2067
  CrossrefPubMedGoogle Scholar
• 60 Villanueva A, Chiang DY, Newell P , et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 2008; 135 (6) 1972-1983 , e1–e11
  CrossrefPubMedGoogle Scholar
• 61 Roessler S, Jia H-L, Budhu A , et al. A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients. Cancer Res 2010; 70 (24) 10202-10212
  CrossrefPubMedGoogle Scholar
• 62 van Malenstein H, Gevaert O, Libbrecht L , et al. A seven-gene set associated with chronic hypoxia of prognostic importance in hepatocellular carcinoma. Clin Cancer Res 2010; 16 (16) 4278-4288
  CrossrefPubMedGoogle Scholar
• 63 Kaposi-Novak P, Lee J-S, Gòmez-Quiroz L, Coulouarn C, Factor VM, Thorgeirsson SS. Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J Clin Invest 2006; 116 (6) 1582-1595
  CrossrefPubMedGoogle Scholar
• 64 Lee J-S, Heo J, Libbrecht L , et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 2006; 12 (4) 410-416
  CrossrefPubMedGoogle Scholar
• 65 Yamashita T, Forgues M, Wang W , et al. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res 2008; 68 (5) 1451-1461
  CrossrefPubMedGoogle Scholar
• 66 Andersen JB, Loi R, Perra A , et al. Progenitor-derived hepatocellular carcinoma model in the rat. Hepatology 2010; 51 (4) 1401-1409
  CrossrefPubMedGoogle Scholar
• 67 Woo HG, Lee JH, Yoon JH , et al. Identification of a cholangiocarcinoma-like gene expression trait in hepatocellular carcinoma. Cancer Res 2010; 70 (8) 3034-3041
  CrossrefPubMedGoogle Scholar
• 68 Durnez A, Verslype C, Nevens F , et al. The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. A possible progenitor cell origin. Histopathology 2006; 49 (2) 138-151
  CrossrefPubMedGoogle Scholar
• 69 Giordano S, Columbano A. MicroRNAs: new tools for diagnosis, prognosis, and therapy in hepatocellular carcinoma?. Hepatology 2013; 57 (2) 840-847
  CrossrefPubMedGoogle Scholar
• 70 Jiang J, Gusev Y, Aderca I , et al. Association of MicroRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival. Clin Cancer Res 2008; 14 (2) 419-427
  CrossrefPubMedGoogle Scholar
• 71 Viswanathan SR, Powers JT, Einhorn W , et al. Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet 2009; 41 (7) 843-848
  CrossrefPubMedGoogle Scholar
• 72 Wei R, Huang GL, Zhang MY , et al. Clinical significance and prognostic value of microRNA expression signatures in hepatocellular carcinoma. Clin Cancer Res 2013; 19 (17) 4780-4791
  CrossrefPubMedGoogle Scholar
• 73 Budhu A, Jia H-L, Forgues M , et al. Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology 2008; 47 (3) 897-907
  CrossrefPubMedGoogle Scholar
• 74 Ji J, Shi J, Budhu A , et al. MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med 2009; 361 (15) 1437-1447
  CrossrefPubMedGoogle Scholar
• 75 Singh S, Singh PP, Roberts LR, Sanchez W. Chemopreventive strategies in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2014; 11 (1) 45-54
  PubMedGoogle Scholar
• 76 Llovet JM, Hernandez-Gea V. Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design. Clin Cancer Res 2014; 20 (8) 2072-2079
  CrossrefPubMedGoogle Scholar
• 77 Cardoso F, Van't Veer L, Rutgers E, Loi S, Mook S, Piccart-Gebhart MJ. Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol 2008; 26 (5) 729-735
  CrossrefPubMedGoogle Scholar
• 78 Baccarani M, Deininger MW, Rosti G , et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122 (6) 872-884
  CrossrefPubMedGoogle Scholar
• 79 Jackson SE, Chester JD. Personalised cancer medicine. Int J Cancer 2014; [Epub ahead of print]PubMed
  PubMedGoogle Scholar
• 80 Villanueva A, Llovet JM. Liver cancer in 2013: Mutational landscape of HCC—the end of the beginning. Nat Rev Clin Oncol 2014; 11 (2) 73-74
  PubMedGoogle Scholar
• 81 Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004; 10 (8) 789-799
  CrossrefPubMedGoogle Scholar
• 82 Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz Jr LA, Kinzler KW. Cancer genome landscapes. Science 2013; 339 (6127) 1546-1558
  CrossrefPubMedGoogle Scholar
• 83 Guichard C, Amaddeo G, Imbeaud S , et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet 2012; 44 (6) 694-698
  CrossrefPubMedGoogle Scholar
• 84 Fujimoto A, Totoki Y, Abe T , et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet 2012; 44 (7) 760-764
  CrossrefPubMedGoogle Scholar
• 85 Ruden M, Puri N. Novel anticancer therapeutics targeting telomerase. Cancer Treat Rev 2013; 39 (5) 444-456
  CrossrefPubMedGoogle Scholar
• 86 Calvisi DF, Ladu S, Gorden A , et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 2006; 130 (4) 1117-1128
  CrossrefPubMedGoogle Scholar
• 87 Newell P, Toffanin S, Villanueva A , et al. Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo. J Hepatol 2009; 51 (4) 725-733
  CrossrefPubMedGoogle Scholar
• 88 Tovar V, Alsinet C, Villanueva A , et al. IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. J Hepatol 2010; 52 (4) 550-559
  PubMedGoogle Scholar
• 89 Santoro A, Rimassa L, Borbath I , et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol 2013; 14 (1) 55-63
  CrossrefPubMedGoogle Scholar
• 90 Xiang Q, Chen W, Ren M , et al. Cabozantinib suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of VEGFR2 and MET. Clin Cancer Res 2014; 20 (11) 2959-2970
  CrossrefPubMedGoogle Scholar
• 91 Goyal L, Muzumdar MD, Zhu AX. Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clin Cancer Res 2013; 19 (9) 2310-2318
  CrossrefPubMedGoogle Scholar
• 92 Sawey ET, Chanrion M, Cai C , et al. Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell 2011; 19 (3) 347-358
  CrossrefPubMedGoogle Scholar
• 93 Chiang DY, Villanueva A, Hoshida Y , et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res 2008; 68 (16) 6779-6788
  CrossrefPubMedGoogle Scholar
• 94 Fernandez-Banet J, Lee NP, Chan KT , et al. Decoding complex patterns of genomic rearrangement in hepatocellular carcinoma. Genomics 2014; 103 (2-3) 189-203
  CrossrefPubMedGoogle Scholar
• 95 Horwitz E, Stein I, Andreozzi M , et al. Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discov 2014; 4 (6) 730-743
  CrossrefPubMedGoogle Scholar
• 96 Cheng A-L, Shen Y-C, Zhu AX. Targeting fibroblast growth factor receptor signaling in hepatocellular carcinoma. Oncology 2011; 81 (5–6) 372-380
  CrossrefPubMedGoogle Scholar
• 97 Lin C-P, Liu C-R, Lee C-N, Chan T-S, Liu HE. Targeting c-Myc as a novel approach for hepatocellular carcinoma. World J Hepatol 2010; 2 (1) 16-20
  PubMedGoogle Scholar
• 98 Stefanska B, Cheishvili D, Suderman M , et al. Genome-wide study of hypomethylated and induced genes in liver cancer patients unravels novel anticancer targets. Clin Cancer Res 2014; 20 (12) 3118-3132
  CrossrefPubMedGoogle Scholar
• 99 Mudbhary R, Hoshida Y, Chernyavskaya Y , et al. UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma. Cancer Cell 2014; 25 (2) 196-209
  CrossrefPubMedGoogle Scholar
• 100 Shen Y-C, Lin Z-Z, Hsu C-H, Hsu C, Shao Y-Y, Cheng A-L. Clinical trials in hepatocellular carcinoma: an update. Liver Cancer 2013; 2 (3-4) 345-364
  CrossrefPubMedGoogle Scholar
• 101 Lachenmayer A, Toffanin S, Cabellos L , et al. Combination therapy for hepatocellular carcinoma: additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib. J Hepatol 2012; 56 (6) 1343-1350
  CrossrefPubMedGoogle Scholar
• 102 Toffanin S, Hoshida Y, Lachenmayer A , et al. MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a. Gastroenterology 2011; 140 (5) 1618-1628 , e16
  CrossrefPubMedGoogle Scholar
• 103 Ling H, Fabbri M, Calin GA. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov 2013; 12 (11) 847-865
  CrossrefPubMedGoogle Scholar
• 104 Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 2010; 10 (11) 760-774
  CrossrefPubMedGoogle Scholar
• 105 Sullivan RJ, Flaherty KT. Resistance to BRAF-targeted therapy in melanoma. Eur J Cancer 2013; 49 (6) 1297-1304
  CrossrefPubMedGoogle Scholar
• 106 Clifford RJ, Zhang J, Meerzaman DM , et al. Genetic variations at loci involved in the immune response are risk factors for hepatocellular carcinoma. Hepatology 2010; 52 (6) 2034-2043
  CrossrefPubMedGoogle Scholar
• 107 Huang J, Deng Q, Wang Q , et al. Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma. Nat Genet 2012; 44 (10) 1117-1121
  CrossrefPubMedGoogle Scholar
• 108 Li M, Zhao H, Zhang X , et al. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet 2011; 43 (9) 828-829
  CrossrefPubMedGoogle Scholar
• 109 Cleary SP, Jeck WR, Zhao X , et al. Identification of driver genes in hepatocellular carcinoma by exome sequencing. Hepatology 2013; 58 (5) 1693-1702
  CrossrefPubMedGoogle Scholar
• 110 Ahn SM, Jang SJ, Shim JH , et al. A genomic portrait of resectable hepatocellular carcinomas: Implications of RB1 and FGF19 aberrations for patient stratification. Hepatology 2014; [Epub ahead of print]PubMed
  PubMedGoogle Scholar
• 111 Sung W-K, Zheng H, Li S , et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet 2012; 44 (7) 765-769
  CrossrefPubMedGoogle Scholar
• 112 Colombino M, Sperlongano P, Izzo F , et al. BRAF and PIK3CA genes are somatically mutated in hepatocellular carcinoma among patients from South Italy. Cell Death Dis 2012; 3: e259
  CrossrefPubMedGoogle Scholar
• 113 Jiang J-H, Liu Y-F, Ke A-W , et al. Clinical significance of the ubiquitin ligase UBE3C in hepatocellular carcinoma revealed by exome sequencing. Hepatology 2014; 59 (6) 2216-2227
  CrossrefPubMedGoogle Scholar