Download PDF
Digestive Disease Interventions 2017; 01(02): 055-065
DOI: 10.1055/s-0037-1603577
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Genetics of Hepatocellular Carcinoma: Risk Stratification, Clinical Outcome, and Implications for Therapy

Ismail Labgaa
1   Division of Liver Diseases, Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
2   Department of Visceral Surgery, Lausanne University Hospital CHUV, Lausanne, Switzerland
,
Sara Torrecilla
1   Division of Liver Diseases, Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
3   Liver Cancer Translational Research Laboratory, BCLC Group, IDIBAPS, Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain
,
Iris Martinez-Quetglas
1   Division of Liver Diseases, Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
3   Liver Cancer Translational Research Laboratory, BCLC Group, IDIBAPS, Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain
,
Daniela Sia
1   Division of Liver Diseases, Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
› Author Affiliations
Further Information

Publication History

27 December 2016

25 April 2017

Publication Date:
05 June 2017 (online)

Also available at
    Permissions and Reprints

Abstract

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a highly heterogeneous disease with a dismal prognosis. During the last decade, significant efforts to elucidate the genetic background of HCC have led to the identification of the major genomic aberrations driving the disease. Nonetheless, only few of them (∼30%) are currently amenable for treatment. Two clear-cut gene expression based HCC molecular classes, namely “proliferation” and “nonproliferation,” have been described. The “proliferation” class is characterized by enrichment in poor prognostic signatures, a more aggressive phenotype, and poorer outcome. In addition, exposure-specific mutational patterns have been identified (smoking, alcohol, aflatoxin B, etc.), whereas molecular signatures from the surrounding cirrhotic liver and single nucleotide polymorphisms have been linked with HCC occurrence. Despite such advances, no molecular biomarker has yet been incorporated in clinical decision-making. In this review, the authors summarize the most recent molecular findings in HCC pointing toward prospects for translating this knowledge into specific clinical interventions.

Keywords

liver cancer - genomics - precision medicine - heterogeneity - molecular classes - prognosis
 

  • References

  • 1 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
  • 2 DeSantis CE, Lin CC, Mariotto AB. , et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin 2014; 64 (04) 252-271
    CrossrefPubMedGoogle Scholar
  • 3 Murray CJ, Vos T, Lozano R. , et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380 (9859): 2197-2223
    CrossrefPubMedGoogle Scholar
  • 4 Llovet JM, Villanueva A, Lachenmayer A, Finn RS. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol 2015; 12 (08) 436
    PubMedGoogle Scholar
  • 5 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 (17) 1625-1638
    CrossrefPubMedGoogle Scholar
  • 6 White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 2012; 10 (12) 1342-1359.e2
    CrossrefPubMedGoogle Scholar
  • 7 Llovet JM, Ricci S, Mazzaferro V. , et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359 (04) 378-390
    CrossrefPubMedGoogle Scholar
  • 8 Bruix J, Qin S, Merle P. , et al; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 389 (10064): 56-66
    CrossrefPubMedGoogle Scholar
  • 9 Llovet JM, Zucman-Rossi J, Pikarsky E. , et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2016; 2: 16018
    CrossrefPubMedGoogle Scholar
  • 10 Marquardt JU, Seo D, Andersen JB. , et al. Sequential transcriptome analysis of human liver cancer indicates late stage acquisition of malignant traits. J Hepatol 2014; 60 (02) 346-353
    CrossrefPubMedGoogle Scholar
  • 11 Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 2006; 6 (09) 674-687
    CrossrefPubMedGoogle Scholar
  • 12 Bartosch B, Thimme R, Blum HE, Zoulim F. Hepatitis C virus-induced hepatocarcinogenesis. J Hepatol 2009; 51 (04) 810-820
    CrossrefPubMedGoogle Scholar
  • 13 Günes C, Rudolph KL. The role of telomeres in stem cells and cancer. Cell 2013; 152 (03) 390-393
    CrossrefPubMedGoogle Scholar
  • 14 Kotoula V, Hytiroglou P, Pyrpasopoulou A, Saxena R, Thung SN, Papadimitriou CS. Expression of human telomerase reverse transcriptase in regenerative and precancerous lesions of cirrhotic livers. Liver 2002; 22 (01) 57-69
    CrossrefPubMedGoogle Scholar
  • 15 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
    CrossrefPubMedGoogle Scholar
  • 16 Nault JC, Calderaro J, Di Tommaso L. , et al. Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis. Hepatology 2014; 60 (06) 1983-1992
    CrossrefPubMedGoogle Scholar
  • 17 Totoki Y, Tatsuno K, Covington KR. , et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet 2014; 46 (12) 1267-1273
    CrossrefPubMedGoogle Scholar
  • 18 Sung WK, Zheng H, Li S. , et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet 2012; 44 (07) 765-769
    CrossrefPubMedGoogle Scholar
  • 19 Kaposi-Novak P, Libbrecht L, Woo HG. , et al. Central role of c-Myc during malignant conversion in human hepatocarcinogenesis. Cancer Res 2009; 69 (07) 2775-2782
    CrossrefPubMedGoogle Scholar
  • 20 Wurmbach E, Chen YB, Khitrov G. , et al. Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology 2007; 45 (04) 938-947
    CrossrefPubMedGoogle Scholar
  • 21 Neuveut C, Wei Y, Buendia MA. Mechanisms of HBV-related hepatocarcinogenesis. J Hepatol 2010; 52 (04) 594-604
    CrossrefPubMedGoogle Scholar
  • 22 Wang J, Chenivesse X, Henglein B, Bréchot C. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature 1990; 343 (6258): 555-557
    CrossrefPubMedGoogle Scholar
  • 23 Nault JC, Datta S, Imbeaud S. , et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet 2015; 47 (10) 1187-1193
    CrossrefPubMedGoogle Scholar
  • 24 Wogan GN. Aflatoxins as risk factors for hepatocellular carcinoma in humans. Cancer Res 1992; 52 (7, Suppl): 2114s-2118s
    PubMedGoogle Scholar
  • 25 Schulze K, Imbeaud S, Letouzé E. , et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet 2015; 47 (05) 505-511
    CrossrefPubMedGoogle Scholar
  • 26 Poon SL, Pang ST, McPherson JR. , et al. Genome-wide mutational signatures of aristolochic acid and its application as a screening tool. Sci Transl Med 2013; 5 (197) 197ra101
    CrossrefPubMedGoogle Scholar
  • 27 Ruden M, Puri N. Novel anticancer therapeutics targeting telomerase. Cancer Treat Rev 2013; 39 (05) 444-456
    CrossrefPubMedGoogle Scholar
  • 28 Paterlini-Bréchot P, Saigo K, Murakami Y. , et al. Hepatitis B virus-related insertional mutagenesis occurs frequently in human liver cancers and recurrently targets human telomerase gene. Oncogene 2003; 22 (25) 3911-3916
    CrossrefPubMedGoogle Scholar
  • 29 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
  • 30 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 (6317): 429-431
    CrossrefPubMedGoogle Scholar
  • 31 Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC. Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 1991; 350 (6317): 427-428
    CrossrefPubMedGoogle Scholar
  • 32 Kan Z, Zheng H, Liu X. , et al. Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res 2013; 23 (09) 1422-1433
    CrossrefPubMedGoogle Scholar
  • 33 Ahn SM, Jang SJ, Shim JH. , et al. Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. Hepatology 2014; 60 (06) 1972-1982
    CrossrefPubMedGoogle Scholar
  • 34 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 (06) 694-698
    CrossrefPubMedGoogle Scholar
  • 35 Li M, Zhao H, Zhang X. , et al. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet 2011; 43 (09) 828-829
    CrossrefPubMedGoogle Scholar
  • 36 Wong CM, Wei L, Law CT. , et al. Up-regulation of histone methyltransferase SETDB1 by multiple mechanisms in hepatocellular carcinoma promotes cancer metastasis. Hepatology 2016; 63 (02) 474-487
    CrossrefPubMedGoogle Scholar
  • 37 Fei Q, Shang K, Zhang J. , et al. Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53. Nat Commun 2015; 6: 8651
    CrossrefPubMedGoogle Scholar
  • 38 Sporn MB, Liby KT. NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer 2012; 12 (08) 564-571
    CrossrefPubMedGoogle Scholar
  • 39 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 (03) 347-358
    CrossrefPubMedGoogle Scholar
  • 40 Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 2015; 149 (05) 1226-1239.e4
    CrossrefPubMedGoogle Scholar
  • 41 Villanueva A, Chiang DY, Newell P. , et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 2008; 135 (06) 1972-1983 , 1983.e1–1983.e11
    CrossrefPubMedGoogle Scholar
  • 42 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 (04) 550-559
    CrossrefPubMedGoogle Scholar
  • 43 Goyal L, Muzumdar MD, Zhu AX. Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clin Cancer Res 2013; 19 (09) 2310-2318
    CrossrefPubMedGoogle Scholar
  • 44 Kaposi-Novak P, Lee JS, 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 (06) 1582-1595
    CrossrefPubMedGoogle Scholar
  • 45 Nicholes K, Guillet S, Tomlinson E. , et al. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol 2002; 160 (06) 2295-2307
    CrossrefPubMedGoogle Scholar
  • 46 Hagel M, Miduturu C, Sheets M. , et al. First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway. Cancer Discov 2015; 5 (04) 424-437
    CrossrefPubMedGoogle Scholar
  • 47 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 (06) 730-743
    CrossrefPubMedGoogle Scholar
  • 48 Martinez-Quetglas I, Pinyol R, Dauch D. , et al. IGF2 is up-regulated by epigenetic mechanisms in hepatocellular carcinomas and is an actionable oncogene product in experimental models. Gastroenterology 2016; 151 (06) 1192-1205
    CrossrefPubMedGoogle Scholar
  • 49 Villanueva A, Alsinet C, Yanger K. , et al. Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology 2012; 143 (06) 1660-1669.e7
    CrossrefPubMedGoogle Scholar
  • 50 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 (06) 2059-2067
    CrossrefPubMedGoogle Scholar
  • 51 Hoshida Y, Nijman SM, Kobayashi M. , et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res 2009; 69 (18) 7385-7392
    CrossrefPubMedGoogle Scholar
  • 52 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 (01) 42-52
    CrossrefPubMedGoogle Scholar
  • 53 Lee JS, Chu IS, Heo J. , et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology 2004; 40 (03) 667-676
    CrossrefPubMedGoogle Scholar
  • 54 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 (04) 725-733
    CrossrefPubMedGoogle Scholar
  • 55 Villanueva A, Hoshida Y, Battiston C. , et al. Combining clinical, pathology, and gene expression data to predict recurrence of hepatocellular carcinoma. Gastroenterology 2011; 140 (05) 1501-12.e2
    CrossrefPubMedGoogle Scholar
  • 56 Yamashita T, Forgues M, Wang W. , et al. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res 2008; 68 (05) 1451-1461
    CrossrefPubMedGoogle Scholar
  • 57 Lachenmayer A, Alsinet C, Savic R. , et al. Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. Clin Cancer Res 2012; 18 (18) 4997-5007
    CrossrefPubMedGoogle Scholar
  • 58 Yamashita T, Wang XW. Cancer stem cells in the development of liver cancer. J Clin Invest 2013; 123 (05) 1911-1918
    CrossrefPubMedGoogle Scholar
  • 59 Villanueva A, Portela A, Sayols S. , et al; HEPTROMIC Consortium. DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma. Hepatology 2015; 61 (06) 1945-1956
    CrossrefPubMedGoogle Scholar
  • 60 Toffanin S, Hoshida Y, Lachenmayer A. , et al. MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a. Gastroenterology 2011; 140 (05) 1618-28.e16
    CrossrefPubMedGoogle Scholar
  • 61 European Association for 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 (04) 908-943
    CrossrefPubMedGoogle Scholar
  • 62 Bruix J, Sherman M. ; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53 (03) 1020-1022
    CrossrefPubMedGoogle Scholar
  • 63 van Meer S, de Man RA, Coenraad MJ. , et al. Surveillance for hepatocellular carcinoma is associated with increased survival: results from a large cohort in the Netherlands. J Hepatol 2015; 63 (05) 1156-1163
    CrossrefPubMedGoogle Scholar
  • 64 Davila JA, Henderson L, Kramer JR. , et al. Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States. Ann Intern Med 2011; 154 (02) 85-93
    CrossrefPubMedGoogle Scholar
  • 65 Goossens N, Labgaa I, Villanueva A. Nontumor prognostic factors in hepatocellular carcinoma. In: Carr BI. , ed. Hepatocellular Carcinoma: Diagnosis and Treatment. Third ed: Springer; 2016: 139-147
    Google Scholar
  • 66 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
  • 67 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
  • 68 Okamoto M, Utsunomiya T, Wakiyama S. , et al. Specific gene-expression profiles of noncancerous liver tissue predict the risk for multicentric occurrence of hepatocellular carcinoma in hepatitis C virus-positive patients. Ann Surg Oncol 2006; 13 (07) 947-954
    CrossrefPubMedGoogle Scholar
  • 69 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
  • 70 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
  • 71 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
  • 72 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 (06) 2034-2043
    CrossrefPubMedGoogle Scholar
  • 73 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
  • 74 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
  • 75 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
  • 76 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
  • 77 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
  • 78 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
  • 79 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
  • 80 Hoshida Y, Moeini A, Alsinet C, Kojima K, Villanueva A. Gene signatures in the management of hepatocellular carcinoma. Semin Oncol 2012; 39 (04) 473-485
    CrossrefPubMedGoogle Scholar
  • 81 van de Vijver MJ, He YD, van't Veer LJ. , et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 2002; 347 (25) 1999-2009
    CrossrefPubMedGoogle Scholar
  • 82 Duffy MJ, O'Donovan N, McDermott E, Crown J. Validated biomarkers: the key to precision treatment in patients with breast cancer. Breast 2016; 29: 192-201
    CrossrefPubMedGoogle Scholar
  • 83 Cardoso F, van't Veer LJ, Bogaerts J. , et al; MINDACT Investigators. 70-Gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med 2016; 375 (08) 717-729
    CrossrefPubMedGoogle Scholar
  • 84 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 (01) 176-187
    CrossrefPubMedGoogle Scholar
  • 85 Chapman PB, Hauschild A, Robert C. , et al; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364 (26) 2507-2516
    CrossrefPubMedGoogle Scholar
  • 86 Shaw AT, Kim DW, Nakagawa K. , et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368 (25) 2385-2394
    CrossrefPubMedGoogle Scholar
  • 87 Piotrowska Z, Niederst MJ, Karlovich CA. , et al. Heterogeneity underlies the emergence of EGFRT790 wild-type clones following treatment of T790M-positive cancers with a third-generation EGFR inhibitor. Cancer Discov 2015; 5 (07) 713-722
    CrossrefPubMedGoogle Scholar
  • 88 Moeini A, Hoeflich K, Pinyol R. , et al. FGF19 immunostaining as biomarker for trial enrichment testing FGFR4 inhibitors in HCC. Hepatology 2016; 64: 601-810
    CrossrefPubMedGoogle Scholar
  • 89 Llovet JM, Peña CE, Lathia CD, Shan M, Meinhardt G, Bruix J. ; SHARP Investigators Study Group. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res 2012; 18 (08) 2290-2300
    CrossrefPubMedGoogle Scholar
  • 90 Siegel AB, Cohen EI, Ocean A. , et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 2008; 26 (18) 2992-2998
    CrossrefPubMedGoogle Scholar
  • 91 Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer 2013; 13 (01) 11-26
    CrossrefPubMedGoogle Scholar
  • 92 Inoki K, Corradetti MN, Guan KL. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 2005; 37 (01) 19-24
    CrossrefPubMedGoogle Scholar
  • 93 Zhu AX, Kudo M, Assenat E. , et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA 2014; 312 (01) 57-67
    CrossrefPubMedGoogle Scholar
  • 94 Llovet JM MP, Weiss KH. et al. Phase II Studies with Refametinib or Refematinib Plus Sorafenib in Patients with Mutant RAS Hepatocellular Carcinoma (HCC). Hepatology 2016; 64: 601-810
    CrossrefPubMedGoogle Scholar
  • 95 Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med 2016; 8 (328) 328rv4
    CrossrefPubMedGoogle Scholar
  • 96 Robert C, Long GV, Brady B. , et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372 (04) 320-330
    CrossrefPubMedGoogle Scholar
  • 97 Chen Y, Ramjiawan RR, Reiberger T. , et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology 2015; 61 (05) 1591-1602
    CrossrefPubMedGoogle Scholar
  • 98 Sangro B, Melero I, Yau TC. , et al. Safety and antitumour activity of nivolumab (nivo) in patients with advanced hepatocellular carcinoma (hcc): interim analysis of dose-expansion cohorts from the phase 1/2 Checkmate-040. Study. 10th ILCA Annual Conference, Vancouver, Canada
    PubMedGoogle Scholar
  • 99 Sia D, Jiao Y, Martinez-Quetglas I. , et al. Molecular characterization of the immune class of hepatocellular carcinoma. Hepatology 2016; 64: 136-361
    CrossrefPubMedGoogle Scholar
  • 100 McGranahan N, Swanton C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell 2015; 27 (01) 15-26
    CrossrefPubMedGoogle Scholar
  • 101 Alizadeh AA, Aranda V, Bardelli A. , et al. Toward understanding and exploiting tumor heterogeneity. Nat Med 2015; 21 (08) 846-853
    CrossrefPubMedGoogle Scholar
  • 102 Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz Jr LA, Kinzler KW. Cancer genome landscapes. Science 2013; 339 (6127): 1546-1558
    CrossrefPubMedGoogle Scholar
  • 103 McGranahan N, Favero F, de Bruin EC, Birkbak NJ, Szallasi Z, Swanton C. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Sci Transl Med 2015; 7 (283) 283ra54
    CrossrefPubMedGoogle Scholar
  • 104 Kenmochi K, Sugihara S, Kojiro M. Relationship of histologic grade of hepatocellular carcinoma (HCC) to tumor size, and demonstration of tumor cells of multiple different grades in single small HCC. Liver 1987; 7 (01) 18-26
    PubMedGoogle Scholar
  • 105 An FQ, Matsuda M, Fujii H. , et al. Tumor heterogeneity in small hepatocellular carcinoma: analysis of tumor cell proliferation, expression and mutation of p53 AND beta-catenin. Int J Cancer 2001; 93 (04) 468-474
    CrossrefPubMedGoogle Scholar
  • 106 Friemel J, Rechsteiner M, Frick L. , et al. Intratumor heterogeneity in hepatocellular carcinoma. Clin Cancer Res 2015; 21 (08) 1951-1961
    CrossrefPubMedGoogle Scholar
  • 107 Shi JY, Xing Q, Duan M. , et al. Inferring the progression of multifocal liver cancer from spatial and temporal genomic heterogeneity. Oncotarget 2016; 7 (03) 2867-2877
    CrossrefPubMedGoogle Scholar
  • 108 Gao Q, Wang ZC, Duan M. , et al. Cell culture system for analysis of genetic heterogeneity within hepatocellular carcinomas and response to pharmacologic agents. Gastroenterology 2017; 152 (01) 232-242.e4
    CrossrefPubMedGoogle Scholar
  • 109 Craig AJ, Ahsen M, Villacorta-Martin C. , et al. Multi-regional integrative genomic analysis reveals intra-tumor heterogeneity in a subset of hepatocellular carcinoma. Hepatology 2016; 64: 136-361
    CrossrefPubMedGoogle Scholar
  • 110 Ng IO, Guan XY, Poon RT, Fan ST, Lee JM. Determination of the molecular relationship between multiple tumour nodules in hepatocellular carcinoma differentiates multicentric origin from intrahepatic metastasis. J Pathol 2003; 199 (03) 345-353
    CrossrefPubMedGoogle Scholar
  • 111 Miao R, Luo H, Zhou H. , et al. Identification of prognostic biomarkers in hepatitis B virus-related hepatocellular carcinoma and stratification by integrative multi-omics analysis. J Hepatol 2014; 61 (04) 840-849
    CrossrefPubMedGoogle Scholar
  • 112 Xue R, Li R, Guo H. , et al. Variable intra-tumor genomic heterogeneity of multiple lesions in patients with hepatocellular carcinoma. Gastroenterology 2016; 150 (04) 998-1008
    CrossrefPubMedGoogle Scholar
  • 113 Sia D HA Zhang Z. , et al. Molecular heterogeneity in multinodular hepatocellular carcinoma. Hepatology 2015; 62: 33A-92A
    CrossrefPubMedGoogle Scholar
  • 114 Ling S, Hu Z, Yang Z. , et al. Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution. Proc Natl Acad Sci U S A 2015; 112 (47) E6496-E6505
    CrossrefPubMedGoogle Scholar
  • 115 Hou Y, Guo H, Cao C. , et al. Single-cell triple omics sequencing reveals genetic, epigenetic, and transcriptomic heterogeneity in hepatocellular carcinomas. Cell Res 2016; 26 (03) 304-319
    CrossrefPubMedGoogle Scholar
  • 116 Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol 2013; 10 (08) 472-484
    CrossrefPubMedGoogle Scholar
  • 117 Labgaa I, Villanueva A. Liquid biopsy in liver cancer. Discov Med 2015; 19 (105) 263-273
    PubMedGoogle Scholar
  • 118 Sun YF, Xu Y, Yang XR. , et al. Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection. Hepatology 2013; 57 (04) 1458-1468
    CrossrefPubMedGoogle Scholar
  • 119 Ono A, Fujimoto A, Yamamoto Y. , et al. Circulating tumor DNA analysis for liver cancers and its usefulness as a liquid biopsy. Cell Mol Gastroenterol Hepatol 2015; 1 (05) 516-534
    PubMedGoogle Scholar
  • 120 Labgaa I, Villacorta MC, D'Avola D. , et al. Ultra-deep sequencing of circulating tumor DNA identifies druggable mutations: exploring applications of a liquid biopsy in HCC. Hepatology 2016; 64: 601-810
    CrossrefPubMedGoogle Scholar
  • 121 Xu Y, Bu X, Dai C, Shang C. High serum microRNA-122 level is independently associated with higher overall survival rate in hepatocellular carcinoma patients. Tumour Biol 2015; 36 (06) 4773-4776
    CrossrefPubMedGoogle Scholar
  • 122 Köberle V, Kronenberger B, Pleli T. , et al. Serum microRNA-1 and microRNA-122 are prognostic markers in patients with hepatocellular carcinoma. Eur J Cancer 2013; 49 (16) 3442-3449
    CrossrefPubMedGoogle Scholar