Skip to main content
SpringerLink
Log in

Diagnostic and Prognostic Performance of Liquid Biopsy in Hepatocellular Carcinoma

  • Chapter
  • First Online:
Liquid Biopsy in Cancer Patients

Part of the book series: Current Clinical Pathology ((CCPATH))

Abstract

Liver cancer is currently the second leading cause of cancer-related deaths worldwide. A majority of patients are diagnosed at intermediate or advanced stage and are no longer candidates for curative treatment. Molecular characterization of the tumor would presumably provide valuable insights for developing novel treatments, but tissue samples are difficult to obtain, especially for nonsurgical patients. Therefore, liquid biopsy represents a noninvasive means to access the genomic information of the tumor and can easily be repeated to monitor tumor evolution. Recent technological progress and preliminary results suggest that liquid biopsy could play a central role in the future management of liver cancer.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

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(2):87–108.

    Article  PubMed  Google Scholar 

  2. DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 2014;64(4):252–71.

    Article  PubMed  Google Scholar 

  3. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, 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):2197–223.

    Article  PubMed  Google 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(8):436.

    Article  PubMed  Google 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):1625–38.

    Article  PubMed  Google 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):1342–59.e2.

    Article  PubMed  PubMed Central  Google Scholar 

  7. European Association For The Study Of The L, European Organisation For R, Treatment Of C. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908–43.

    Article  Google Scholar 

  8. Bruix J, Sherman M, American Association for the Study of Liver D. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1020–2.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.

    Article  CAS  PubMed  Google Scholar 

  10. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G; 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 Jan 7;389(10064):56–66.

    Google Scholar 

  11. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245–55.

    Article  PubMed  Google Scholar 

  12. Villanueva A, Portela A, Sayols S, Battiston C, Hoshida Y, Mendez-Gonzalez J, et al. DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma. Hepatology. 2015;61(6):1945–56.

    Article  CAS  PubMed  Google Scholar 

  13. Villanueva A, Hoshida Y, Battiston C, Tovar V, Sia D, Alsinet C, et al. Combining clinical, pathology, and gene expression data to predict recurrence of hepatocellular carcinoma. Gastroenterology. 2011;140(5):1501–12.e2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385–94.

    Article  CAS  PubMed  Google Scholar 

  15. Friemel J, Rechsteiner MP, Frick L, Boehm F, Struckmann K, Sigg M, et al. Intratumor heterogeneity in hepatocellular carcinoma. Clin Cancer Res. 2015;21(8):1951–61.

    Article  CAS  PubMed  Google Scholar 

  16. Schulze K, Imbeaud S, Letouze E, Alexandrov LB, Calderaro J, Rebouissou S, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47(5):505–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Villanueva A, Llovet JM. Liver cancer in 2013: mutational landscape of HCC–the end of the beginning. Nat Rev Clin Oncol. 2014;11(2):73–4.

    Article  CAS  PubMed  Google Scholar 

  18. Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology. 2015;149(5):1226–39.e4.

    Article  CAS  PubMed  Google Scholar 

  19. Labgaa I, Villanueva A. Liquid biopsy in liver cancer. Discov Med. 2015;19(105):263–73.

    PubMed  Google Scholar 

  20. Xu W, Cao L, Chen L, Li J, Zhang XF, Qian HH, et al. Isolation of circulating tumor cells in patients with hepatocellular carcinoma using a novel cell separation strategy. Clin Cancer Res. 2011;17(11):3783–93.

    Article  PubMed  Google Scholar 

  21. Jackson PE, Qian GS, Friesen MD, Zhu YR, Lu P, Wang JB, et al. Specific p53 mutations detected in plasma and tumors of hepatocellular carcinoma patients by electrospray ionization mass spectrometry. Cancer Res. 2001;61(1):33–5.

    CAS  PubMed  Google Scholar 

  22. Zhang YJ, Wu HC, Shen J, Ahsan H, Tsai WY, Yang HI, et al. Predicting hepatocellular carcinoma by detection of aberrant promoter methylation in serum DNA. Clin Cancer Res. 2007;13(8):2378–84.

    Article  CAS  PubMed  Google Scholar 

  23. Huang ZH, Hu Y, Hua D, Wu YY, Song MX, Cheng ZH. Quantitative analysis of multiple methylated genes in plasma for the diagnosis and prognosis of hepatocellular carcinoma. Exp Mol Pathol. 2011;91(3):702–7.

    Article  CAS  PubMed  Google Scholar 

  24. Wen L, Li J, Guo H, Liu X, Zheng S, Zhang D, et al. Genome-scale detection of hypermethylated CpG islands in circulating cell-free DNA of hepatocellular carcinoma patients. Cell Res. 2015;25(11):1250–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Qi P, Cheng SQ, Wang H, Li N, Chen YF, Gao CF. Serum microRNAs as biomarkers for hepatocellular carcinoma in Chinese patients with chronic hepatitis B virus infection. PLoS One. 2011;6(12):e28486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tomimaru Y, Eguchi H, Nagano H, Wada H, Kobayashi S, Marubashi S, et al. Circulating microRNA-21 as a novel biomarker for hepatocellular carcinoma. J Hepatol. 2012;56(1):167–75.

    Article  CAS  PubMed  Google Scholar 

  27. Lin XJ, Chong Y, Guo ZW, Xie C, Yang XJ, Zhang Q, et al. A serum microRNA classifier for early detection of hepatocellular carcinoma: a multicentre, retrospective, longitudinal biomarker identification study with a nested case-control study. Lancet Oncol. 2015;16(7):804–15.

    Article  CAS  PubMed  Google Scholar 

  28. Vona G, Estepa L, Beroud C, Damotte D, Capron F, Nalpas B, et al. Impact of cytomorphological detection of circulating tumor cells in patients with liver cancer. Hepatology. 2004;39(3):792–7.

    Article  PubMed  Google Scholar 

  29. Sun YF, Xu Y, Yang XR, Guo W, Zhang X, Qiu SJ, 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(4):1458–68.

    Article  CAS  PubMed  Google Scholar 

  30. Fan ST, Yang ZF, Ho DW, Ng MN, Yu WC, Wong J. Prediction of posthepatectomy recurrence of hepatocellular carcinoma by circulating cancer stem cells: a prospective study. Ann Surg. 2011;254(4):569–76.

    Article  PubMed  Google Scholar 

  31. Cheng SW, Tsai HW, Lin YJ, Cheng PN, Chang YC, Yen CJ, et al. Lin28B is an oncofetal circulating cancer stem cell-like marker associated with recurrence of hepatocellular carcinoma. PLoS One. 2013;8(11):e80053.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Liu S, Li N, Yu X, Xiao X, Cheng K, Hu J, et al. Expression of intercellular adhesion molecule 1 by hepatocellular carcinoma stem cells and circulating tumor cells. Gastroenterology. 2013;144(5):1031–41.e10.

    Article  PubMed  Google Scholar 

  33. Li J, Shi L, Zhang X, Sun B, Yang Y, Ge N, et al. pERK/pAkt phenotyping in circulating tumor cells as a biomarker for sorafenib efficacy in patients with advanced hepatocellular carcinoma. Oncotarget. 2015;7(3):2646–59.

    Article  CAS  PubMed Central  Google Scholar 

  34. Ono A, Fujimoto A, Yamamoto Y, Akamatsu S, Hiraga N, Imamura M, et al. Circulating tumor DNA analysis for liver cancers and its usefulness as a liquid biopsy. Cell Mol Gastroenterol Hepatol. 2015;1:516–34.

    Article  PubMed  PubMed Central  Google Scholar 

  35. 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(6):4773–6.

    Article  CAS  PubMed  Google Scholar 

  36. Koberle V, Kronenberger B, Pleli T, Trojan J, Imelmann E, Peveling-Oberhag J, et al. Serum microRNA-1 and microRNA-122 are prognostic markers in patients with hepatocellular carcinoma. Eur J Cancer. 2013;49(16):3442–9.

    Article  PubMed  Google Scholar 

  37. Wei JX, Lv LH, Wan YL, Cao Y, Li GL, Lin HM, et al. Vps4A functions as a tumor suppressor by regulating the secretion and uptake of exosomal microRNAs in human hepatoma cells. Hepatology. 2015;61(4):1284–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ronot M, Vilgrain V. Hepatocellular carcinoma: diagnostic criteria by imaging techniques. Best Pract Res Clin Gastroenterol. 2014;28(5):795–812.

    Article  PubMed  Google Scholar 

  39. Pantel K, Brakenhoff RH, Brandt B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer. 2008;8(5):329–40.

    Article  CAS  PubMed  Google Scholar 

  40. Waguri N, Suda T, Nomoto M, Kawai H, Mita Y, Kuroiwa T, et al. Sensitive and specific detection of circulating cancer cells in patients with hepatocellular carcinoma; detection of human telomerase reverse transcriptase messenger RNA after immunomagnetic separation. Clin Cancer Res. 2003;9(8):3004–11.

    CAS  PubMed  Google Scholar 

  41. Nel I, Baba HA, Ertle J, Weber F, Sitek B, Eisenacher M, et al. Individual profiling of circulating tumor cell composition and therapeutic outcome in patients with hepatocellular carcinoma. Transl Oncol. 2013;6(4):420–8.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Schulze K, Gasch C, Staufer K, Nashan B, Lohse AW, Pantel K, et al. Presence of EpCAM-positive circulating tumor cells as biomarker for systemic disease strongly correlates to survival in patients with hepatocellular carcinoma. Int J Cancer. 2013;133(9):2165–71.

    Article  CAS  PubMed  Google Scholar 

  43. Dent BM, Ogle LF, O’Donnell RL, Hayes N, Malik U, Curtin NJ, et al. High-resolution imaging for the detection and characterisation of circulating tumour cells from patients with oesophageal, hepatocellular, thyroid and ovarian cancers. Int J Cancer. 2016;138(1):206–16.

    Article  CAS  PubMed  Google Scholar 

  44. Kelley RK, Magbanua MJ, Butler TM, Collisson EA, Hwang J, Sidiropoulos N, et al. Circulating tumor cells in hepatocellular carcinoma: a pilot study of detection, enumeration, and next-generation sequencing in cases and controls. BMC Cancer. 2015;15:206.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Li J, Chen L, Zhang X, Zhang Y, Liu H, Sun B, et al. Detection of circulating tumor cells in hepatocellular carcinoma using antibodies against asialoglycoprotein receptor, carbamoyl phosphate synthetase 1 and pan-cytokeratin. PLoS One. 2014;9(4):e96185.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Yamashita T, Forgues M, Wang W, Kim JW, Ye Q, Jia H, et al. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res. 2008;68(5):1451–61.

    Article  CAS  PubMed  Google Scholar 

  47. Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11(6):426–37.

    Article  CAS  PubMed  Google Scholar 

  48. Chiang DY, Villanueva A, Hoshida Y, Peix J, Newell P, Minguez B, et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res. 2008;68(16):6779–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Jiang P, Chan CW, Chan KC, Cheng SH, Wong J, Wong VW, et al. Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients. Proc Natl Acad Sci U S A. 2015;112(11):E1317–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sun K, Jiang P, Chan KC, Wong J, Cheng YK, Liang RH, et al. Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments. Proc Natl Acad Sci U S A. 2015;112(40):E5503–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hosny G, Farahat N, Tayel H, Hainaut P. Ser-249 TP53 and CTNNB1 mutations in circulating free DNA of Egyptian patients with hepatocellular carcinoma versus chronic liver diseases. Cancer Lett. 2008;264(2):201–8.

    Article  CAS  PubMed  Google Scholar 

  52. Masyuk AI, Masyuk TV, Larusso NF. Exosomes in the pathogenesis, diagnostics and therapeutics of liver diseases. J Hepatol. 2013;59(3):621–5.

    Article  CAS  PubMed  Google Scholar 

  53. Enache LS, Enache EL, Ramiere C, Diaz O, Bancu L, Sin A, et al. Circulating RNA molecules as biomarkers in liver disease. Int J Mol Sci. 2014;15(10):17644–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Eccles SA, Welch DR. Metastasis: recent discoveries and novel treatment strategies. Lancet. 2007;369(9574):1742–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Liu CL, Fan ST, Cheung ST, Lo CM, Ng IO, Wong J. Anterior approach versus conventional approach right hepatic resection for large hepatocellular carcinoma: a prospective randomized controlled study. Ann Surg. 2006;244(2):194–203.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Toso C, Mentha G, Majno P. Liver transplantation for hepatocellular carcinoma: five steps to prevent recurrence. Am J Transplant. 2011;11(10):2031–5.

    Article  CAS  PubMed  Google Scholar 

  57. Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3(6):453–8.

    Article  CAS  PubMed  Google Scholar 

  58. Fan JL, Yang YF, Yuan CH, Chen H, Wang FB. Circulating cumor cells for predicting the prognostic of patients with hepatocellular carcinoma: a meta analysis. Cell Physiol Biochem. 2015;37(2):629–40.

    Article  CAS  PubMed  Google Scholar 

  59. Hoshida Y, Moeini A, Alsinet C, Kojima K, Villanueva A. Gene signatures in the management of hepatocellular carcinoma. Semin Oncol. 2012;39(4):473–85.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Jill Gregory for her design support with Figs. 14.1 and 14.2. IL is supported by Foundation Roberto & Gianna Gonella, SICPA Foundation, and the Swiss National Science Foundation (SNF). AV is the recipient of the American Association for the Study of Liver Diseases (AASLD) Foundation Alan Hofmann Clinical and Translational Award. AV is supported by the U.S. Department of Defense (CA150272P3) and the Tisch Cancer Institute.

Disclosure

The authors report no conflicts of interest.

Author information

Authors and Affiliations

  1. Division of Liver Diseases, Liver Cancer Program, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Ismail Labgaa MD, Amanda J. Craig BS & Augusto Villanueva MD, PhD

  2. Division of Visceral Surgery, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

    Ismail Labgaa MD

  3. Division of Hematology/Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Augusto Villanueva MD, PhD

Authors
  1. Ismail Labgaa MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amanda J. Craig BS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Augusto Villanueva MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Augusto Villanueva MD, PhD .

Editor information

Editors and Affiliations

  1. College of Science and Technology, Temple University Sbarro Institute for Cancer Research, Philadelphia, Pennsylvania, USA

    Antonio Russo

  2. Surgical and Oncological Sciences, University of Palermo School of Medicine, Palermo, Italy

    Antonio Giordano

  3. Oncology, University Hospital Antwerp, Edegem, Antwerpen, Belgium

    Christian Rolfo

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Labgaa, I., Craig, A.J., Villanueva, A. (2017). Diagnostic and Prognostic Performance of Liquid Biopsy in Hepatocellular Carcinoma. In: Russo, A., Giordano, A., Rolfo, C. (eds) Liquid Biopsy in Cancer Patients. Current Clinical Pathology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-55661-1_14

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-55661-1_14

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-55659-8

  • Online ISBN: 978-3-319-55661-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation