Skip to main content

Advertisement

SpringerLink
Log in

Genomic Landscape of HCC

  • Hepatic Cancer (N Parikh, Section Editor)
  • Published:
Current Hepatology Reports Aims and scope Submit manuscript

Abstract

Introduction

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in the world, and it has limited treatment options. Understanding the molecular drivers of HCC is important to develop novel biomarkers and therapeutics.

Purpose of Review

HCC arises in a complex background of chronic hepatitis, fibrosis, and liver regeneration which lead to genomic changes. Here, we summarize studies that have expanded our understanding of the molecular landscape of HCC.

Recent Findings

Recent technological advances in next-generation sequencing (NGS) have elucidated specific genetic and molecular programs involved in hepatocarcinogenesis. We summarize the major somatic mutations and epigenetic changes have been identified in NGS-based studies. We also describe promising molecular therapies and immunotherapies which target specific genetic and epigenetic molecular events.

Summary

The genomic landscape of HCC is incredibly complex and heterogeneous. Promising new developments are helping us decipher the molecular drivers of HCC and leading to new therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

2D LC-MS/MS:

Multidimensional liquid chromatography-tandem mass spectrometry

AFP:

Alpha-fetoprotein

ALD:

Alcoholic liver disease

ALL:

Acute lymphoblastic leukemia

ATM:

Ataxia telangiectasia mutated

CDH1:

Cadherin-1

CNV:

Copy number variations

DFS:

Disease-free survival

DNMTs:

DNA methyltransferases

FDA:

Food and Drug Administration

GOF:

Gain of function

HATs:

Histone acetyltransferases

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

hCSC:

Hepatic cancer stem cell

HCV:

Hepatitis C virus

HDACs:

Histone deacetylases

HDAC3:

Histone deacetylase 3

JAKs:

Janus kinases

lncRNAs:

Long non-coding RNAs

LT:

Liver transplantation

MAT1A:

Methionine adenosyltransferase 1

MMP9:

Matrix metalloproteinase-9

miRNAs:

MicroRNAs

NAFLD:

Nonalcoholic fatty liver disease

NGS:

Next-generation sequencing

NF-KB:

Nuclear factor-𝜅 beta

OS:

Overall survival

PLEC1:

Plectin 1

PRC1:

Protein regulator of cytokinesis 1

SCNAs:

Somatic copy number alterations

scRNA-Seq:

Single-cell RNA sequencing

TACE:

Transarterial chemoembolization

TCGA:

The Cancer Genome Atlas

TERC:

Telomerase RNA component

TERT:

Telomerase reverse transcriptase

TF:

Transcription factor

TOP2A:

Topoisomerase 2 𝛼

JAKs:

Transmembrane receptor Janus kinases

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    PubMed  Google Scholar 

  2. Valery PC, Laversanne M, Clark PJ, Petrick JL, McGlynn KA, Bray F. Projections of primary liver cancer to 2030 in 30 countries worldwide. Hepatology. 2018;67:600–11.

    PubMed  Google Scholar 

  3. Seegobin K, Majeed U, Ritter A, Wylie N, Starr JS, Jones JC, et al. Factors affecting time to treatment in hepatocellular cancer. J Clin Oncol. 2020;38:e19088.

    Google Scholar 

  4. Huang Y-T, Jen C-L, Yang H-I, Lee M-H, Su J, Lu S-N, et al. Lifetime risk and sex difference of hepatocellular carcinoma among patients with chronic hepatitis B and C. J Clin Oncol. 2011;29:3643–50.

    PubMed  PubMed Central  Google Scholar 

  5. Baumert TF, Jühling F, Ono A, Hoshida Y. Hepatitis C-related hepatocellular carcinoma in the era of new generation antivirals. BMC Med. 2017;15:52.

    PubMed  PubMed Central  Google Scholar 

  6. Marengo A, Rosso C, Bugianesi E. Liver cancer: connections with obesity, fatty liver, and cirrhosis. Annu Rev Med. 2016;67:103–17.

    CAS  PubMed  Google Scholar 

  7. Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol. 2013;47(Suppl):S2–6.

    PubMed  PubMed Central  Google Scholar 

  8. Park EJ, Lee JH, Yu G-Y, 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Zámbó V, Simon-Szabó L, Szelényi P, Kereszturi É, Bánhegyi G, Csala M. Lipotoxicity in the liver. World J Hepatol. 2013;5:550.

    PubMed  PubMed Central  Google Scholar 

  10. Rowe J, Ghouri Y, Mian I. Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis. Journal of Carcinogenesis. 2017;16:1.

    PubMed  PubMed Central  Google Scholar 

  11. Do AL, Wong CR, Nguyen LH, Nguyen VG, Trinh H, Nguyen MH. Hepatocellular carcinoma incidence in noncirrhotic patients with chronic hepatitis B and patients with cirrhosis of all etiologies. J Clin Gastroenterol. 2014;48:644–9.

    PubMed  Google Scholar 

  12. Tobari M, Hashimoto E, Taniai M, Kodama K, Kogiso T, Tokushige K, et al. The characteristics and risk factors of hepatocellular carcinoma in nonalcoholic fatty liver disease without cirrhosis. J Gastroenterol Hepatol. 2020;35:862–9.

    PubMed  Google Scholar 

  13. Menahem B, Lubrano J, Duvoux C, Mulliri A, Alves A, Costentin C, et al. Liver transplantation versus liver resection for hepatocellular carcinoma in intention to treat: an attempt to perform an ideal meta-analysis. Liver Transpl. 2017;23:836–44.

    PubMed  Google Scholar 

  14. Tang W, Chen Z, Zhang W, Cheng Y, Zhang B, Wu F, et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther. 2020;5:87.

    PubMed  PubMed Central  Google Scholar 

  15. Marisi G, Cucchetti A, Ulivi P, Canale M, Cabibbo G, Solaini L, et al. Ten years of sorafenib in hepatocellular carcinoma: are there any predictive and/or prognostic markers? World J Gastroenterol. 2018;24:4152–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Krishnamoorthy SK, Relias V, Sebastian S, Jayaraman V, Saif MW. Management of regorafenib-related toxicities: a review. Ther Adv Gastroenterol. 2015;8:285–97.

    CAS  Google Scholar 

  17. Xu W, Liu K, Chen M, Sun J-Y, McCaughan GW, Lu X-J, et al. Immunotherapy for hepatocellular carcinoma: recent advances and future perspectives. Ther Adv Med Oncol. 2019;11:1758835919862692.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Personeni N, Pressiani T, Rimassa L. Lenvatinib for the treatment of unresectable hepatocellular carcinoma: evidence to date. J Hepatocell Carcinoma. 2019;6:31–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhan P, Ji Y-N. Prognostic significance of TP53 expression for patients with hepatocellular carcinoma: a meta-analysis. Hepatobiliary Surg Nutr. 2014;3:11–7.

    PubMed  PubMed Central  Google Scholar 

  20. Ma Z, Guo D, Wang Q, Liu P, Xiao Y, Wu P, et al. Lgr5-mediated p53 repression through PDCD5 leads to doxorubicin resistance in hepatocellular carcinoma. Theranostics. 2019;9:2967–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Kancherla V, Abdullazade S, Matter MS, Lanzafame M, Quagliata L, Roma G, et al. Genomic analysis revealed new oncogenic signatures in TP53-mutant hepatocellular carcinoma. Front Genet. 2018;9. https://doi.org/10.3389/fgene.2018.00002.

  22. Zhu Z-Z, Bao L-L, Zhao K, Xu Q, Zhu JY, Zhu KX, et al. Copy number aberrations of multiple genes identified as prognostic markers for extrahepatic metastasis-free survival of patients with hepatocellular carcinoma. Curr Med Sci. 2019;39:759–65.

    CAS  PubMed  Google Scholar 

  23. Long J, Wang A, Bai Y, Lin J, Yang X, Wang D, et al. Development and validation of a TP53-associated immune prognostic model for hepatocellular carcinoma. EBioMedicine. 2019;42:363–74.

    PubMed  PubMed Central  Google Scholar 

  24. Qu Y-L, Deng C-H, Luo Q, Shang X-Y, Wu J-X, Shi Y, et al. Arid1a regulates insulin sensitivity and lipid metabolism. EBioMedicine. 2019;42:481–93.

    PubMed  PubMed Central  Google Scholar 

  25. MultiVir, Inc. Safety and efficacy of p53 gene therapy 684 combined with immune checkpoint Q7 inhibitors in solid tumors. Identifier NCT03544723. 2018. https://clinicaltrials.gov/ct2/show/NCT03544723.

  26. Huang C-Y, Hsieh F-S, Wang C-Y, Chen LJ, Chang SS, Tsai MH, et al. Palbociclib enhances radiosensitivity of hepatocellular carcinoma and cholangiocarcinoma via inhibiting ataxia telangiectasia–mutated kinase–mediated DNA damage response. Eur J Cancer. 2018;102:10–22.

    CAS  PubMed  Google Scholar 

  27. Samstein RM, Lee C-H, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51:202–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Nault J-C, Zucman-Rossi J. TERT promoter mutations in primary liver tumors. Clin Res Hepatol Gastroenterol. 2016;40:9–14.

    CAS  PubMed  Google Scholar 

  29. Torrecilla S, Sia D, Harrington AN, Zhang Z, Cabellos L, Cornella H, et al. Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma. J Hepatol. 2017;67:1222–31.

    PubMed  Google Scholar 

  30. Nault JC, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, Laurent C, et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun. 2013;4:2218.

    PubMed  PubMed Central  Google Scholar 

  31. Donaires FS, Scatena NF, Alves-Paiva RM, Podlevsky JD, Logeswaran D, Santana BA, et al. Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma. PLoS One. 2017;12:e0183287.

    PubMed  PubMed Central  Google Scholar 

  32. Pezzuto F, Buonaguro L, Buonaguro FM, Tornesello ML. Frequency and geographic distribution of TERT promoter mutations in primary hepatocellular carcinoma. Infect Agent Cancer. 2017;12:27.

    PubMed  PubMed Central  Google Scholar 

  33. Zulehner G, Mikula M, Schneller D, van Zijl F, Huber H, Sieghart W, et al. Nuclear beta-catenin induces an early liver progenitor phenotype in hepatocellular carcinoma and promotes tumor recurrence. Am J Pathol. 2010;176:472–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Pezzuto F, Izzo F, Buonaguro L, Annunziata C, Tatangelo F, Botti G, et al. Tumor specific mutations in TERT promoter and CTNNB1 gene in hepatitis B and hepatitis C related hepatocellular carcinoma. Oncotarget. 2016;7:54253–62.

    PubMed  PubMed Central  Google Scholar 

  35. Khalaf AM, Fuentes D, Morshid AI, Burke MR, Kaseb AO, Hassan M, et al. Role of Wnt/β-catenin signaling in hepatocellular carcinoma, pathogenesis, and clinical significance. Journal of Hepatocellular Carcinoma. 2018;5:61–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Li P, Cao Y, Li Y, Zhou L, Liu X, Geng M. Expression of Wnt-5a and β-catenin in primary hepatocellular carcinoma. Int J Clin Exp Pathol. 2014;7:3190–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Ataide EC, Perales SR, Silva MG, Filho FC, Sparapani AC, Latuf Filho PF, et al. Immunoexpression of heat shock protein 70, glypican 3, glutamine synthetase, and beta-catenin in hepatocellular carcinoma after liver transplantation: association between positive glypican 3 and beta-catenin with the presence of larger nodules. Transplant Proc. 2017;49:858–62.

    CAS  PubMed  Google Scholar 

  38. Vonderheide R, McRee A, Johnson J, Shields A, Bahary N, Chintakuntlawar A. Pharmaceuticals I (2016) hTERT immunotherapy alone or in combination with IL-12 DNA followed by electroporation in 734 adults with solid tumors at high risk of relapse (TRT-001). Identifier NCT02960594. https://clinicaltrials.gov/ct2/show/NCT02960594.

  39. Trung NT, Hoan NX, Trung PQ, Binh MT, Van Tong H, Toan NL, et al. Clinical significance of combined circulating TERT promoter mutations and miR-122 expression for screening HBV-related hepatocellular carcinoma. Sci Rep. 2020;10:8181.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Waisberg J. Wnt−/−β-catenin pathway signaling in human hepatocellular carcinoma. World J Hepatol. 2015;7:2631.

    PubMed  PubMed Central  Google Scholar 

  41. Yuan K, Xie K, Lan T, Xu L, Chen X, Li X, et al. TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of β-catenin. Cell Death Differ. 2020;27:1355–68.

    CAS  PubMed  Google Scholar 

  42. Cui Y, Wu X, Lin C, Zhang X, Ye L, Ren L, et al. AKIP1 promotes early recurrence of hepatocellular carcinoma through activating the Wnt/β-catenin/CBP signaling pathway. Oncogene. 2019;38:5516–29.

    CAS  PubMed  Google Scholar 

  43. Hechtman JF, Abou-Alfa GK, Stadler ZK, Mandelker DL, Roehrl MHA, Zehir A, et al. Somatic HNF1A mutations in the malignant transformation of hepatocellular adenomas: a retrospective analysis of data from MSK-IMPACT and TCGA. Hum Pathol. 2019;83:1–6.

    CAS  PubMed  Google Scholar 

  44. Rebouissou S, Imbeaud S, Balabaud C, Boulanger V, Bertrand-Michel J, Tercé F, et al. HNF1alpha inactivation promotes lipogenesis in human hepatocellular adenoma independently of SREBP-1 and carbohydrate-response element-binding protein (ChREBP) activation. J Biol Chem. 2007;282:14437–46.

    CAS  PubMed  Google Scholar 

  45. Xiong S, Wang R, Chen Q, Luo J, Wang J, Zhao Z, et al. Cancer-associated fibroblasts promote stem cell-like properties of hepatocellular carcinoma cells through IL-6/STAT3/Notch signaling. Am J Cancer Res. 2018;8:302–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Bi Y-H, Han W-Q, Li R-F, Wang Y-J, Du Z-S, Wang X-J, et al. Signal transducer and activator of transcription 3 promotes the Warburg effect possibly by inducing pyruvate kinase M2 phosphorylation in liver precancerous lesions. World J Gastroenterol. 2019;25:1936–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Huang L, Jian Z, Gao Y, Zhou P, Zhang G, Jiang B, et al. RPN2 promotes metastasis of hepatocellular carcinoma cell and inhibits autophagy via STAT3 and NF-κB pathways. Aging. 2019;11:6674–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Yang L, Zhang X-Y, Li K, Li AP, Yang WD, Yang R, et al. Protopanaxadiol inhibits epithelial-mesenchymal transition of hepatocellular carcinoma by targeting STAT3 pathway. Cell Death Dis. 2019;10:630.

    PubMed  PubMed Central  Google Scholar 

  49. Xu G, Zhu L, Wang Y, Shi Y, Gong A, Wu C. Stattic enhances radiosensitivity and reduces radio-induced migration and invasion in HCC cell lines through an apoptosis pathway. Biomed Res Int. 2017;2017:1832494.

    PubMed  PubMed Central  Google Scholar 

  50. Yoo C, Kang J, Kim K-P, Lim HY, Kim JH, Lee MA, et al. Phase I dose-finding study of OPB-111077, a novel STAT3 inhibitor, in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2018;36:4078.

    Google Scholar 

  51. Okusaka T, Ueno H, Ikeda M, Mitsunaga S, Ozaka M, Ishii H, et al. Phase 1 and pharmacological trial of OPB-31121, a signal transducer and activator of transcription-3 inhibitor, in patients with advanced hepatocellular carcinoma. Hepatol Res. 2015;45:1283–91.

    CAS  PubMed  Google Scholar 

  52. Shitara K, Yodo Y, Iino S. A phase I study of Napabucasin plus paclitaxel for Japanese patients with advanced/recurrent gastric cancer. In Vivo. 2019;33:933–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Reilley MJ, McCoon P, Cook C, Lyne P, Kurzrock R, Kim Y, et al. STAT3 antisense oligonucleotide AZD9150 in a subset of patients with heavily pretreated lymphoma: results of a phase 1b trial. Journal for ImmunoTherapy of Cancer. 2018;6:119. https://doi.org/10.1186/s40425-018-0436-5.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Cheng J, Wei D, Ji Y, Chen L, Yang L, Li G, et al. Integrative analysis of DNA methylation and gene expression reveals hepatocellular carcinoma-specific diagnostic biomarkers. Genome Med. 2018;10:42.

    PubMed  PubMed Central  Google Scholar 

  55. Lee S, Lee HJ, Kim J-H, Lee H-S, Jang JJ, Kang GH. Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol. 2003;163:1371–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Wu X, Yao X, Cao Q, Wu Z, Wang Z, Liu F, et al. Clinicopathological and prognostic significance of CDH1 hypermethylation in hepatocellular carcinoma: a meta-analysis. Cancer Manag Res. 2019;11:857–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Gailhouste L, Liew LC, Yasukawa K, Hatada I, Tanaka Y, Nakagama H, et al. Differentiation therapy by epigenetic reconditioning exerts antitumor effects on liver cancer cells. Mol Ther. 2018;26:1840–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Liu J, Liu Y, Meng L, Liu K, Ji B. Targeting the PD-L1/DNMT1 axis in acquired resistance to sorafenib in human hepatocellular carcinoma. Oncol Rep. 2017;38:899–907.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Jueliger S, Lyons J, Cannito S, Pata I, Pata P, Shkolnaya M, et al. Efficacy and epigenetic interactions of novel DNA hypomethylating agent guadecitabine (SGI-110) in preclinical models of hepatocellular carcinoma. Epigenetics. 2016;11:709–20.

    PubMed  PubMed Central  Google Scholar 

  60. Xu X, Tao Y, Shan L, Chen R, Jiang H, Qian Z, et al. The role of MicroRNAs in hepatocellular carcinoma. J Cancer. 2018;9:3557–69.

    PubMed  PubMed Central  Google Scholar 

  61. Chen S-Y, Ma D-N, Chen Q-D, Zhang J-J, Tian Y-R, Wang Z-C, et al. MicroRNA-200a inhibits cell growth and metastasis by targeting Foxa2 in hepatocellular carcinoma. J Cancer. 2017;8:617–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Moshiri F, Callegari E, D’Abundo L, Corrà F, Lupini L, Sabbioni S, et al. Inhibiting the oncogenic mir-221 by microRNA sponge: toward microRNA-based therapeutics for hepatocellular carcinoma. Gastroenterol Hepatol Bed Bench. 2014;7:43–54.

    PubMed  PubMed Central  Google Scholar 

  63. Li S-P, Xu H-X, Yu Y, et al. LncRNA HULC enhances epithelial-mesenchymal transition to promote tumorigenesis and metastasis of hepatocellular carcinoma via the miR-200a-3p/ZEB1 signaling pathway. Oncotarget. 2016;7:42431–46.

    PubMed  PubMed Central  Google Scholar 

  64. Fujisaka Y, Iwata T, Tamai K, Nakamura M, Mochizuki M, Shibuya R, et al. Long non-coding RNA HOTAIR up-regulates chemokine (C-C motif) ligand 2 and promotes proliferation of macrophages and myeloid-derived suppressor cells in hepatocellular carcinoma cell lines. Oncol Lett. 2017. https://doi.org/10.3892/ol.2017.7322.

  65. van der Ree MH, van der Meer AJ, van Nuenen AC, de Bruijne J, Ottosen S, Janssen HL, et al. Miravirsen dosing in chronic hepatitis C patients results in decreased microRNA-122 levels without affecting other microRNAs in plasma. Aliment Pharmacol Ther. 2016;43:102–13.

    PubMed  Google Scholar 

  66. Voi M, Fu S, Nemunaitis J, Bauman J, Bessudo A, Hamid O, et al. 590 final results of a phase Ib study of CUDC-101, a multitargeted inhibitor of EGFR, HER2, and HDAC, in patients with advanced head and neck, gastric, breast, liver, and non-small cell lung cancer. Eur J Cancer. 2012;48:181.

    Google Scholar 

  67. Yeo W, Chung HC, Chan SL, Wang LZ, Lim R, Picus J, et al. Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo phase II consortium and the Cancer Therapeutics Research Group. J Clin Oncol. 2012;30:3361–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Mani SKK, Zhang H, Diab A, Pascuzzi PE, Lefrançois L, Fares N, et al. EpCAM-regulated intramembrane proteolysis induces a cancer stem cell-like gene signature in hepatitis B virus-infected hepatocytes. J Hepatol. 2016;65:888–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Chao J, Zhao S, Sun H. Dedifferentiation of hepatocellular carcinoma: molecular mechanisms and therapeutic implications. Am J Transl Res. 2020;12:2099–109.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Muramatsu S, Tanaka S, Mogushi K, Adikrisna R, Aihara A, Ban D, et al. Visualization of stem cell features in human hepatocellular carcinoma reveals in vivo significance of tumor-host interaction and clinical course. Hepatology. 2013;58:218–28.

    CAS  PubMed  Google Scholar 

  71. Ye C, Zhang X, Chen X, Cao Q, Zhang X, Zhou Y, et al. Multiple novel hepatocellular carcinoma signature genes are commonly controlled by the master pluripotency factor OCT4. Cell Oncol. 2020;43:279–95.

    CAS  Google Scholar 

  72. Zhang B-H, Yang J, Jiang L, Lyu T, Kong LX, Tan YF, et al. Development and validation of a 14-gene signature for prognosis prediction in hepatocellular carcinoma. Genomics. 2020;112:2763–71.

    CAS  PubMed  Google Scholar 

  73. Zhang J, Baddoo M, Han C, Strong MJ, Cvitanovic J, Moroz K, et al. Gene network analysis reveals a novel 22-gene signature of carbon metabolism in hepatocellular carcinoma. Oncotarget. 2016;7:49232–45.

    PubMed  PubMed Central  Google Scholar 

  74. Li N, Zhao L, Guo C, Liu C, Liu Y. Identification of a novel DNA repair-related prognostic signature predicting survival of patients with hepatocellular carcinoma. Cancer Manag Res. 2019;11:7473–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Chan L-K, Ng IO-L. Proteomic profiling in liver cancer: another new page. Transl Gastroenterol Hepatol. 2019;4:47.

    PubMed  PubMed Central  Google Scholar 

  76. He Y, Luo Y, Zhang D, Wang X, Zhang P, Li H, et al. PGK1-mediated cancer progression and drug resistance. Am J Cancer Res. 2019;9:2280–302.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhao Y, Li Y, Liu W, Xing S, Wang D, Chen J, et al. Identification of noninvasive diagnostic biomarkers for hepatocellular carcinoma by urinary proteomics. J Proteome. 2020;225:103780.

    CAS  Google Scholar 

  78. Blokzijl F, de Ligt J, Jager M, Sasselli V, Roerink S, Sasaki N, et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature. 2016;538:260–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Brunner SF, Roberts ND, Wylie LA, Moore L, Aitken SJ, Davies SE, et al. Somatic mutations and clonal dynamics in healthy and cirrhotic human liver. Nature. 2019;574:538–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Brazhnik K, Sun S, Alani O, Kinkhabwala M, Wolkoff AW, Maslov AY, et al. Single-cell analysis reveals different age-related somatic mutation profiles between stem and differentiated cells in human liver. Sci Adv. 2020;6:eaax2659.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Yu L-X, Ling Y, Wang H-Y. Role of nonresolving inflammation in hepatocellular carcinoma development and progression. NPJ Precis Oncol. 2018;2:6.

    PubMed  PubMed Central  Google Scholar 

  82. Zhang B-L, Ji X, Yu L-X, et al. Somatic mutation profiling of liver and biliary cancer by targeted next generation sequencing. Oncol Lett. 2018;16:6003–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Bouaoun L, Sonkin D, Ardin M, Hollstein M, Byrnes G, Zavadil J, et al. TP53 variations in human cancers: new lessons from the IARC TP53 database and genomics data. Hum Mutat. 2016;37:865–76.

    CAS  PubMed  Google Scholar 

  84. Teramoto T, Satonaka K, Kitazawa S, Fujimori T, Hayashi K, Maeda S. Gene abnormalities are closely related to hepatoviral infections and occur at a late stage of hepatocarcinogenesis. Cancer Res. 1994;54:53.

    Google Scholar 

  85. Zhang W, He H, Zang M, et al. Genetic features of aflatoxin-associated hepatocellular carcinoma. Gastroenterology. 2017;153:249–262.e2.

    CAS  PubMed  Google Scholar 

  86. Chittmittrapap S, Chieochansin T, Chaiteerakij R, Treeprasertsuk S, Klaikaew N, Tangkijvanich P, et al. Prevalence of aflatoxin induced p53 mutation at codon 249 (R249s) in hepatocellular carcinoma patients with and without hepatitis B surface antigen (HBsAg). Asian Pac J Cancer Prev. 2013;14:7675–9.

    PubMed  Google Scholar 

  87. Villanueva A, Hoshida Y. Depicting the role of TP53 in hepatocellular carcinoma progression. J Hepatol. 2011;55:724–5.

    PubMed  Google Scholar 

  88. Liu Y, Yan J, Wang F. Effects of TACE combined with precise RT on p53 gene expression and prognosis of HCC patients. Oncol Lett. 2018;16:5733–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Nahon P, Nault J-C. Constitutional and functional genetics of human alcohol-related hepatocellular carcinoma. Liver Int. 2017;37:1591–601.

    CAS  PubMed  Google Scholar 

  90. Sung W-K, 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.

    CAS  PubMed  Google Scholar 

  91. Moore A, Wu L, Chuang J-C, Sun X, Luo X, Gopal P, et al. Arid1a loss drives nonalcoholic steatohepatitis in mice through epigenetic dysregulation of hepatic lipogenesis and fatty acid oxidation. Hepatology. 2019;69:1931–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Vasileiou G, Ekici AB, Uebe S, Zweier C, Hoyer J, Engels H, et al. Chromatin-remodeling-factor ARID1B represses Wnt/β-catenin signaling. Am J Hum Genet. 2015;97:445–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Li L, Rao X, et al. Implications of driver genes associated with a high tumor mutation burden identified using next-generation sequencing on immunotherapy in hepatocellular carcinoma. Oncol Lett. 2020. https://doi.org/10.3892/ol.2020.11372.

  94. Peng Y, Gao B, Zhou Z, Chen T, Xie W, Huang M, et al. Hepatocellular carcinoma with ARID1A mutation is associated with higher TMB and poor survival. J Clin Oncol. 2020;38:e16667.

    Google Scholar 

  95. Hu C, Li W, Tian F, Jiang K, Liu X, Cen J, et al. Arid1a regulates response to anti-angiogenic therapy in advanced hepatocellular carcinoma. J Hepatol. 2018;68:465–75.

    CAS  PubMed  Google Scholar 

  96. Yu JI, Choi C, Ha SY, Park CK, Kang SY, Joh JW, et al. Clinical importance of TERT overexpression in hepatocellular carcinoma treated with curative surgical resection in HBV endemic area. Sci Rep. 2017;7:12258.

    PubMed  PubMed Central  Google Scholar 

  97. Cheng Y, Huang M, Xie W, Gao C, Cai S, Ji J, et al. Chromosome 8q24 amplification predicts prognosis for patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2019;37:e15654.

    Google Scholar 

  98. Li X, Xu W, Kang W, Wong SH, Wang M, Zhou Y, et al. Genomic analysis of liver cancer unveils novel driver genes and distinct prognostic features. Theranostics. 2018;8:1740–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Jiao J, Watt GP, Stevenson HL, Calderone TL, Fisher-Hoch SP, Ye Y, et al. Telomerase reverse transcriptase mutations in plasma DNA in patients with hepatocellular carcinoma or cirrhosis: prevalence and risk factors. Hepatology Communications. 2018;2:718–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Valenta T, Hausmann G, Basler K. The many faces and functions of β-catenin. EMBO J. 2012;31:2714–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Chen J, Rajasekaran M, Xia H, Zhang X, Kong SN, Sekar K, et al. The microtubule-associated protein PRC1 promotes early recurrence of hepatocellular carcinoma in association with the Wnt/β-catenin signalling pathway. Gut. 2016;65:1522–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Caruso S, Calderaro J, Letouzé E, Nault JC, Couchy G, Boulai A, et al. Germline and somatic DICER1 mutations in familial and sporadic liver tumors. J Hepatol. 2017;66:734–42.

    CAS  PubMed  Google Scholar 

  103. Marquardt JU. DKN-01 Inhibition in Advanced Liver Cancer. Identifier NCT03645980. 2018. https://clinicaltrials.gov/ct2/show/NCT03645980.

  104. Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu, Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell. 2017;169:1327–1341.e23.

    Google Scholar 

  105. Calderaro J, Couchy G, Imbeaud S, Amaddeo G, Letouzé E, Blanc JF, et al. Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. J Hepatol. 2017;67:727–38.

    CAS  PubMed  Google Scholar 

  106. Doycheva I, Thuluvath PJ. Systemic therapy for advanced hepatocellular carcinoma: an update of a rapidly evolving field. J Clin Exp Hepatol. 2019;9:588–96.

    PubMed  PubMed Central  Google Scholar 

  107. Zheng A, Chevalier N, Calderoni M, Dubuis G, Dormond O, Ziros PG, et al. CRISPR/Cas9 genome-wide screening identifies KEAP1 as a sorafenib, lenvatinib, and regorafenib sensitivity gene in hepatocellular carcinoma. Oncotarget. 2019;10:7058–70.

    PubMed  PubMed Central  Google Scholar 

  108. Reznik Y, Dao T, Coutant R, Chiche L, Jeannot E, Clauin S, et al. Hepatocyte nuclear factor-1 alpha gene inactivation: cosegregation between liver adenomatosis and diabetes phenotypes in two maturity-onset diabetes of the young (MODY)3 families. J Clin Endocrinol Metab. 2004;89:1476–80.

    CAS  PubMed  Google Scholar 

  109. Zeng X, Lin Y, Yin C, Zhang X, Ning BF, Zhang Q, et al. Recombinant adenovirus carrying the hepatocyte nuclear factor-1alpha gene inhibits hepatocellular carcinoma xenograft growth in mice. Hepatology. 2011;54:2036–47.

    CAS  PubMed  Google Scholar 

  110. Takashima Y, Horisawa K, Udono M, Ohkawa Y, Suzuki A. Prolonged inhibition of hepatocellular carcinoma cell proliferation by combinatorial expression of defined transcription factors. Cancer Sci. 2018;109:3543–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Kan Z, Zheng H, Liu X, Li S, Barber TD, Gong Z, et al. Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res. 2013;23:1422–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Yin Z, Ma T, Lin Y, Lu X, Zhang C, Chen S, et al. IL-6/STAT3 pathway intermediates M1/M2 macrophage polarization during the development of hepatocellular carcinoma. J Cell Biochem. 2018;119:9419–32.

    CAS  PubMed  Google Scholar 

  113. Ki Kim S, Ueda Y, Hatano E, Kakiuchi N, Takeda H, Goto T, et al. TERT promoter mutations and chromosome 8p loss are characteristic of nonalcoholic fatty liver disease-related hepatocellular carcinoma. Int J Cancer. 2016;139:2512–8.

    PubMed  Google Scholar 

  114. Zhou C, Zhang W, Chen W, Yin Y, Atyah M, Liu S, et al. Integrated analysis of copy number variations and gene expression profiling in hepatocellular carcinoma. Sci Rep. 2017;7:10570.

    PubMed  PubMed Central  Google Scholar 

  115. Schlaeger C, Longerich T, Schiller C, et al. Etiology-dependent molecular mechanisms in human hepatocarcinogenesis. Hepatology. 2008;47:511–20.

    CAS  PubMed  Google Scholar 

  116. Ao L, Song X, Li X, Tong M, Guo Y, Li J, et al. An individualized prognostic signature and multi-omics distinction for early stage hepatocellular carcinoma patients with surgical resection. Oncotarget. 2016;7:24097–110.

    PubMed  PubMed Central  Google Scholar 

  117. Yu M-C, Lee C-W, Lee Y-S, Lian J-H, Tsai C-L, Liu Y-P, et al. Prediction of early-stage hepatocellular carcinoma using OncoScan chromosomal copy number aberration data. World J Gastroenterol. 2017;23:7818–29.

    PubMed  PubMed Central  Google Scholar 

  118. Pedica F, Ruzzenente A, Bagante F, Capelli P, Cataldo I, Pedron S, et al. A re-emerging marker for prognosis in hepatocellular carcinoma: the add-value of fishing c-myc gene for early relapse. PLoS One. 2013;8:e68203.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Kent LN, Bae S, Tsai S-Y, Tang X, Srivastava A, Koivisto C, et al. Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma. J Clin Invest. 2017;127:830–42.

    PubMed  PubMed Central  Google Scholar 

  120. Yu X, Huang J, Wu S, Huang Y, Shan Y, Lu C. Copy number variations of MMP-9 are prognostic biomarkers for hepatocellular carcinoma. Transl Cancer Res. 2020;9:698–706.

    CAS  Google Scholar 

  121. Kawai-Kitahata F, Asahina Y, Tanaka S, Kakinuma S, Murakawa M, Nitta S, et al. Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features. J Gastroenterol. 2016;51:473–86.

    CAS  PubMed  Google Scholar 

  122. Sun S, Li Y, Han S, Jia H, Li X, Li X. A comprehensive genome-wide profiling comparison between HBV and HCV infected hepatocellular carcinoma. BMC Med Genet. 2019;12:147.

    Google Scholar 

  123. Zhang B, Deng C, Wang L, Zhou F, Zhang S, Kang W, et al. Upregulation of UBE2Q1 via gene copy number gain in hepatocellular carcinoma promotes cancer progression through β-catenin-EGFR-PI3K-Akt-mTOR signaling pathway. Mol Carcinog. 2018;57:201–15.

    CAS  PubMed  Google Scholar 

  124. Dong S, Wu Y, Yu S, Yang Y, Lu L, Fan S. Increased EXT1 gene copy number correlates with increased mRNA level predicts short disease-free survival in hepatocellular carcinoma without vascular invasion. Medicine. 2018;97:e12625.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Zhou S-L, Zhou Z-J, Hu Z-Q, Song CL, Luo YJ, Luo CB, et al. Genomic sequencing identifies WNK2 as a driver in hepatocellular carcinoma and a risk factor for early recurrence. J Hepatol. 2019;71:1152–63.

    CAS  PubMed  Google Scholar 

  126. Kaibori M, Sakai K, Ishizaki M, Matsushima H, de Velasco MA, Matsui K, et al. Increased FGF19 copy number is frequently detected in hepatocellular carcinoma with a complete response after sorafenib treatment. Oncotarget. 2016;7:49091–8.

    PubMed  PubMed Central  Google Scholar 

  127. Shen J, Wang S, Zhang Y-J, Kappil M, Wu HC, Kibriya MG, et al. Genome-wide DNA methylation profiles in hepatocellular carcinoma. Hepatology. 2012;55:1799–808.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Gentilini D, Scala S, Gaudenzi G, Garagnani P, Capri M, Cescon M, et al. Epigenome-wide association study in hepatocellular carcinoma: identification of stochastic epigenetic mutations through an innovative statistical approach. Oncotarget. 2017;8:41890–902.

    PubMed  PubMed Central  Google Scholar 

  129. Yang Z, Zhou L, Wu L-M, Lai M-C, Xie H-Y, Zhang F, et al. Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann Surg Oncol. 2011;18:1243–50.

    PubMed  Google Scholar 

  130. Lu X-F, Cao X-Y, Zhu Y-J, Wu ZR, Zhuang X, Shao MY, et al. Histone deacetylase 3 promotes liver regeneration and liver cancer cells proliferation through signal transducer and activator of transcription 3 signaling pathway. Cell Death Dis. 2018;9:398.

    PubMed  PubMed Central  Google Scholar 

  131. Ji H, Zhou Y, Zhuang X, Zhu Y, Wu Z, Lu Y, et al. HDAC3 deficiency promotes liver cancer through a defect in H3K9ac/H3K9me3 transition. Cancer Res. 2019;79:3676–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Yang Y, Zhang J, Wu T, Xu X, Cao G, Li H, et al. Histone deacetylase 2 regulates the doxorubicin (Dox) resistance of hepatocarcinoma cells and transcription of ABCB1. Life Sci. 2019;216:200–6.

    CAS  PubMed  Google Scholar 

  133. Gahr S, Mayr C, Kiesslich T, et al. The pan-deacetylase inhibitor panobinostat affects angiogenesis in hepatocellular carcinoma models via modulation of CTGF expression. Int J Oncol. 2015;47:963–70.

    CAS  PubMed  Google Scholar 

  134. Bitzer M, Horger M, Giannini EG, Ganten TM, Wörns MA, Siveke JT, et al. Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma - the SHELTER study. J Hepatol. 2016;65:280–8.

    CAS  PubMed  Google Scholar 

  135. Lee J-S, Chu I-S, Heo J, Calvisi DF, Sun Z, Roskams T, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004;40:667–76.

    CAS  PubMed  Google Scholar 

  136. Segal E, Friedman N, Koller D, Regev A. A module map showing conditional activity of expression modules in cancer. Nat Genet. 2004;36:1090–8.

    CAS  PubMed  Google Scholar 

  137. Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang H–Y, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009;136:1012–24.

    CAS  PubMed  Google Scholar 

  138. Li Y, Farmer RW, Yang Y, Martin RCG. Epithelial cell adhesion molecule in human hepatocellular carcinoma cell lines: a target of chemoresistence. BMC Cancer. 2016;16:228.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Jiang Y, Sun A, Zhao Y, et al. Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature. 2019;567:257–61.

    CAS  PubMed  Google Scholar 

  140. Gao Q, Zhu H, Dong L, Shi W, Chen R, Song Z, et al. Integrated proteogenomic characterization of HBV-related hepatocellular carcinoma. Cell. 2019;179(2):561–77.

  141. Liu H, Chen H, Wu X, Sun Y, Wang Y, Zeng Y, et al. The serum proteomics tracking of hepatocellular carcinoma early recurrence following radical resection. Cancer Manag Res. 2019;11:2935–46.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Stanford School of Medicine, Stanford, CA, USA

    Nia Adeniji

  2. Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 300 Pasteur Drive, Alway Building M211, Stanford, CA, 94305-5151, USA

    Renumathy Dhanasekaran

Authors
  1. Nia Adeniji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Renumathy Dhanasekaran
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Renumathy Dhanasekaran.

Ethics declarations

Conflict of Interest

No conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Hepatic Cancer

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Adeniji, N., Dhanasekaran, R. Genomic Landscape of HCC. Curr Hepatology Rep 19, 448–461 (2020). https://doi.org/10.1007/s11901-020-00553-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11901-020-00553-7

Keywords

Search

Navigation