Current Hepatology Reports

, Volume 18, Issue 4, pp 390–399 | Cite as

Liquid Biopsy for Hepatocellular Carcinoma

  • Vincent L. ChenEmail author
  • Neehar D. Parikh
Hepatic Cancer (N Parikh, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Hepatic Cancer


Purpose of Review

Clinically available biomarkers for hepatocellular carcinoma (HCC) early diagnosis and prognostication have limited utility. Further lack of routine biopsy in hepatocellular carcinoma limits the availability of molecular information to guide drug development. Recent studies investigating liquid biopsy using circulating tumor cells (CTCs) and cell-free deoxyribonucleic acid (cfDNA) have yielded promising data that could address both of these limitations.

Recent Findings

For early HCC diagnosis, CTCs have modest sensitivity but high specificity. CfDNA methylation scores have shown high sensitivity and specificity in two large phase II studies. Presence of CTCs has been associated with poorer prognosis in numerous studies, particularly increased cancer recurrence following curative therapy, while the literature on cfDNA and prognosis is less robust.


Liquid biopsy using CTCs and cfDNA has shown promise in prognostication and early diagnosis in HCC. Further robust validation of this liquid biopsy is required for routine clinical use.


Circulating tumor cell Cell-free DNA Early diagnosis Biomarker 





Cell-free deoxyribonucleic acid


Circulating tumor cell


Epithelial-mesenchymal transition


Hepatocellular carcinomas


Author Contributions

Vincent Chen: drafting of the manuscript

Neehar Parikh: critical review of manuscript

All authors identified above have critically reviewed the paper and approve the final version of this paper, including the authorship statement.

Funding Information

Vincent Chen was supported in part by a University of Michigan Training in Basic and Translational Digestive Sciences T32 grant (5T32DK094775).

Compliance with Ethical Standards

Conflict of Interest

Vincent Chen declares no potential conflicts of interest.

Neehar Parikh: Consultant: Bristol-Myers Squibb, Exelixis, Freenome; Advisory Board: Eisai, Bayer, Exelixis, Wako Diagnostics; Research Grants: Bayer, Target Pharmasolutions, Exact Sciences.

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.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Bertuccio P, Turati F, Carioli G, Rodriguez T, La Vecchia C, Malvezzi M, et al. Global trends and predictions in hepatocellular carcinoma mortality. J Hepatol. 2017;67(2):302–9.PubMedGoogle Scholar
  2. 2.
    Tandon P, Garcia-Tsao G. Prognostic indicators in hepatocellular carcinoma: a systematic review of 72 studies. Liver Int. 2009;29(4):502–10.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Tapper EB, Parikh ND. Mortality due to cirrhosis and liver cancer in the United States, 1999-2016: observational study. BMJ. 2018;362:k2817.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Tzartzeva K, Obi J, Rich NE, Parikh ND, Marrero JA, Yopp A, et al. Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis. Gastroenterology. 2018;154(6):1706–18.e1.PubMedPubMedCentralGoogle Scholar
  5. 5.
    El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492–502.PubMedGoogle Scholar
  6. 6.
    Bruix J, Qin S, Merle P, Granito A, Huang Y-H, Bodoky G, et al. 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.PubMedGoogle Scholar
  7. 7.
    Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1020–2.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Tapper EB, Lok AS. Use of liver imaging and biopsy in clinical practice. N Engl J Med. 2017;377(8):756–68.PubMedGoogle Scholar
  9. 9.
    Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res. 2004;10(20):6897–904.Google Scholar
  10. 10.
    Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11(6):426–37.Google Scholar
  11. 11.
    Tricoli L, Niture S, Chimeh U, Ressom H, Kumar D. Role of microRNAs in the development of hepatocellular carcinoma and drug resistance. Front Biosci (Landmark Ed). 2019;24:382–91.Google Scholar
  12. 12.
    Wong CM, Tsang FH, Ng IO. Non-coding RNAs in hepatocellular carcinoma: molecular functions and pathological implications. Nat Rev Gastroenterol Hepatol. 2018;15(3):137–51.PubMedGoogle Scholar
  13. 13.
    Wu S, Liu S, Liu Z, Huang J, Pu X, Li J, et al. Classification of circulating tumor cells by epithelial-mesenchymal transition markers. PLoS One. 2015;10(4):e0123976.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Lin E, Rivera-Baez L, Fouladdel S, Yoon HJ, Guthrie S, Wieger J, et al. High-throughput microfluidic labyrinth for the label-free isolation of circulating tumor cells. Cell Syst. 2017;5(3):295–304 e4.Google Scholar
  15. 15.
    Chen VL, Xu D, Harouaka R, Wicha M, Lok A, Parikh ND. Mo1451–liquid biopsy for prognosis in hepatocellular carcinoma (HCC) using circulating tumor cells (CTCS): a systematic review and meta-analysis. Gastroenterology. 2019;156(6):S-1311.Google Scholar
  16. 16.
    Guo BT, Liu XC, Huang Y, Ou HH, Li XH, Yang DH. Positive circulating tumor cells in the peripheral blood may indicate a poor prognosis in patients with hepatocellular carcinoma. Nan Fang Yi Ke Da Xue Xue Bao. 2016;36(8):1134–9.PubMedGoogle Scholar
  17. 17.
    Yu JJ, Xiao W, Dong SL, Liang HF, Zhang ZW, Zhang BX, et al. Effect of surgical liver resection on circulating tumor cells in patients with hepatocellular carcinoma. BMC Cancer. 2018;18(1):835.PubMedPubMedCentralGoogle Scholar
  18. 18.
    •• Sun YF, Guo W, Xu Y, Shi YH, Gong ZJ, Ji Y, et al. Circulating tumor cells from different vascular sites exhibit spatial heterogeneity in epithelial and mesenchymal composition and distinct clinical significance in hepatocellular carcinoma. Clin Cancer Res. 2018;24(3):547–59 Identified that vascular territories have unique prognostic significance, and also discussed circulating tumor clusters. PubMedGoogle Scholar
  19. 19.
    • D'Avola D, Villacorta-Martin C, Martins-Filho SN, Craig A, Labgaa I, von Felden J, et al. High-density single cell mRNA sequencing to characterize circulating tumor cells in hepatocellular carcinoma. Sci Rep. 2018;8(1):11570 Transcriptomic sequencing of circulating tumor cells in hepatocellular carcinoma. PubMedPubMedCentralGoogle Scholar
  20. 20.
    • Bhan I, Mosesso K, Goyal L, Philipp J, Kalinich M, Franses JW, et al. Detection and analysis of circulating epithelial cells in liquid biopsies from patients with liver disease. Gastroenterology. 2018. Transcriptomic sequencing of circulating tumor cells in hepatocellular carcinoma. Google Scholar
  21. 21.
    Kalinich M, Bhan I, Kwan TT, Miyamoto DT, Javaid S, LiCausi JA, et al. An RNA-based signature enables high specificity detection of circulating tumor cells in hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2017;114(5):1123–8.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Guo W, Yang XR, Sun YF, Shen MN, Ma XL, Wu J, et al. Clinical significance of EpCAM mRNA-positive circulating tumor cells in hepatocellular carcinoma by an optimized negative enrichment and qRT-PCR-based platform. Clin Cancer Res. 2014;20(18):4794–805.PubMedGoogle Scholar
  23. 23.
    Yang SZ, Dong JH, Li K, Zhang Y, Zhu J. Detection of AFPmRNA and melanoma antigen gene-1mRNA as markers of disseminated hepatocellular carcinoma cells in blood. Hepatobiliary Pancreat Dis Int. 2005;4(2):227–33.PubMedGoogle Scholar
  24. 24.
    Yao F, Guo JM, Xu CF, Lou YL, Xiao BX, Zhou WH, et al. Detecting AFP mRNA in peripheral blood of the patients with hepatocellular carcinoma, liver cirrhosis and hepatitis. Clin Chim Acta. 2005;361(1–2):119–27.PubMedGoogle Scholar
  25. 25.
    • Guo W, Sun YF, Shen MN, Ma XL, Wu J, Zhang CY, et al. Circulating tumor cells with stem-like phenotypes for diagnosis, prognosis, and therapeutic response evaluation in hepatocellular carcinoma. Clin Cancer Res. 2018;24(9):2203–13.PubMedGoogle Scholar
  26. 26.
    Chen H, Sun LY, Zheng HQ, Zhang QF, Jin XM. Total serum DNA and DNA integrity: diagnostic value in patients with hepatitis B virus-related hepatocellular carcinoma. Pathology. 2012;44(4):318–24.PubMedGoogle Scholar
  27. 27.
    Chen K, Zhang H, Zhang LN, Ju SQ, Qi J, Huang DF, et al. Value of circulating cell-free DNA in diagnosis of hepatocelluar carcinoma. World J Gastroenterol. 2013;19(20):3143–9.PubMedPubMedCentralGoogle Scholar
  28. 28.
    El-Shazly SF, Eid MA, El-Sourogy HA, Attia GF, Ezzat SA. Evaluation of serum DNA integrity as a screening and prognostic tool in patients with hepatitis C virus-related hepatocellular carcinoma. Int J Biol Markers. 2010;25(2):79–86.PubMedGoogle Scholar
  29. 29.
    Huang Z, Hua D, Hu Y, Cheng Z, Zhou X, Xie Q, et al. Quantitation of plasma circulating DNA using quantitative PCR for the detection of hepatocellular carcinoma. Pathol Oncol Res. 2012;18(2):271–6.PubMedGoogle Scholar
  30. 30.
    Iizuka N, Sakaida I, Moribe T, Fujita N, Miura T, Stark M, et al. Elevated levels of circulating cell-free DNA in the blood of patients with hepatitis C virus-associated hepatocellular carcinoma. Anticancer Res. 2006;26(6c):4713–9.PubMedGoogle Scholar
  31. 31.
    Piciocchi M, Cardin R, Vitale A, Vanin V, Giacomin A, Pozzan C, et al. Circulating free DNA in the progression of liver damage to hepatocellular carcinoma. Hepatol Int. 2013;7(4):1050–7.PubMedGoogle Scholar
  32. 32.
    Ren N, Qin LX, Tu H, Liu YK, Zhang BH, Tang ZY. Quantitative analysis of circulating DNA level in plasma from patients with hepatocellular carcinoma and its potential clinical value. Fudan Univ J Med Sci. 2005;32(2):134–8.Google Scholar
  33. 33.
    Yan L, Chen Y, Zhou J, Zhao H, Zhang H, Wang G. Diagnostic value of circulating cell-free DNA levels for hepatocellular carcinoma. Int J Infect Dis. 2018;67:92–7.PubMedGoogle Scholar
  34. 34.
    Huang A, Zhang X, Zhou SL, Cao Y, Huang XW, Fan J, et al. Plasma circulating cell-free DNA integrity as a promising biomarker for diagnosis and surveillance in patients with hepatocellular carcinoma. J Cancer. 2016;7(13):1798–803.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Chang H, Yi B, Li L, Zhang HY, Sun F, Dong SQ, et al. Methylation of tumor associated genes in tissue and plasma samples from liver disease patients. Exp Mol Pathol. 2008;85(2):96–100.PubMedGoogle Scholar
  36. 36.
    Chu HJ, Heo J, Seo SB, Kim GH, Kang DH, Song GA, et al. Detection of aberrant p16INK4A methylation in sera of patients with liver cirrhosis and hepatocellular carcinoma. J Korean Med Sci. 2004;19(1):83–6.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Tan SH, Ida H, Lau QC, Goh BC, Chieng WS, Loh M, et al. Detection of promoter hypermethylation in serum samples of cancer patients by methylation-specific polymerase chain reaction for tumour suppressor genes including RUNX3. Oncol Rep. 2007;18(5):1225–30.PubMedGoogle Scholar
  38. 38.
    Wong IHN, Dennis Lo YM, Zhang J, Liew C-T, Ng MHL, Wong N, et al. Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients. Cancer Res. 1999;59(1):71.PubMedGoogle Scholar
  39. 39.
    Wong IH, Lo YM, Yeo W, Lau WY, Johnson PJ. Frequent p15 promoter methylation in tumor and peripheral blood from hepatocellular carcinoma patients. Clin Cancer Res. 2000;6(9):3516–21.PubMedGoogle Scholar
  40. 40.
    Wong IHN, Johnson PJ, Lai PBS, Lau WY, Lo YMD. Tumor-derived epigenetic changes in the plasma and serum of liver cancer patients: implications for cancer detection and monitoring. Ann N Y Acad Sci. 2000;906(1):102–5.PubMedGoogle Scholar
  41. 41.
    Wong IH, Zhang J, Lai PB, Lau WY, Lo YM. Quantitative analysis of tumor-derived methylated p16INK4a sequences in plasma, serum, and blood cells of hepatocellular carcinoma patients. Clin Cancer Res. 2003;9(3):1047–52.PubMedGoogle Scholar
  42. 42.
    Zhang YJ, Rossner P Jr, Chen Y, Agrawal M, Wang Q, Wang L, et al. Aflatoxin B1 and polycyclic aromatic hydrocarbon adducts, p53 mutations and p16 methylation in liver tissue and plasma of hepatocellular carcinoma patients. Int J Cancer. 2006;119(5):985–91.PubMedGoogle Scholar
  43. 43.
    Huang XH, Sun LH, Lu DD, Sun Y, Ma LJ, Zhang XR, et al. Codon 249 mutation in exon 7 of p53 gene in plasma DNA: maybe a new early diagnostic marker of hepatocellular carcinoma in Qidong risk area, China. World J Gastroenterol. 2003;9(4):692–5.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Igetei R, Otegbayo JA, Ndububa DA, Lesi OA, Anumudu CI, Hainaut P, et al. Detection of p53 codon 249 mutation in Nigerian patients with hepatocellular carcinoma using a novel evaluation of cell-free DNA. Ann Hepatol. 2008;7(4):339–44.PubMedGoogle Scholar
  45. 45.
    Jackson PE, Qian G-S, Friesen MD, Zhu Y-R, Lu P, Wang J-B, 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.PubMedGoogle Scholar
  46. 46.
    Jackson PE, Kuang S-Y, Wang J-B, Strickland PT, Muñoz A, Kensler TW, et al. Prospective detection of codon 249 mutations in plasma of hepatocellular carcinoma patients. Carcinogenesis. 2003;24(10):1657–63.PubMedGoogle Scholar
  47. 47.
    Kirk GD, Lesi OA, Mendy M, Szymañska K, Whittle H, Goedert JJ, et al. 249ser TP53 mutation in plasma DNA, hepatitis B viral infection, and risk of hepatocellular carcinoma. Oncogene. 2005;24(38):5858–67.PubMedGoogle Scholar
  48. 48.
    Liao W, Yang H, Xu H, Wang Y, Ge P, Ren J, et al. Noninvasive detection of tumor-associated mutations from circulating cell-free DNA in hepatocellular carcinoma patients by targeted deep sequencing. Oncotarget. 2016;7(26):40481–90.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Marchio A, Amougou Atsama M, Bere A, Komas NP, Noah Noah D, Atangana PJA, et al. Droplet digital PCR detects high rate of TP53 R249S mutants in cell-free DNA of middle African patients with hepatocellular carcinoma. Clin Exp Med. 2018;18:421–31.PubMedGoogle Scholar
  50. 50.
    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. Hepatol Commun. 2018;2(6):718–31.PubMedPubMedCentralGoogle Scholar
  51. 51.
    • Kisiel JB, Dukek BA, Kanipakam R.V.S.R, Ghoz HM, Yab TC, Berger CK, et al. Hepatocellular carcinoma detection by plasma methylated DNA: discovery, phase I pilot, and phase II clinical validation. Hepatology. 2018;0(0). Large study of circulating tumor DNA for early detection in hepatocellular carcinoma. Google Scholar
  52. 52.
    •• Xu RH, Wei W, Krawczyk M, Wang W, Luo H, Flagg K, et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. Nat Mater. 2017;16(11):1155–61 Largest study to date of circulating tumor DNA for early diagnosis and prognosis in hepatocellular carcinoma. PubMedGoogle Scholar
  53. 53.
    Court CM, Hou S, Winograd P, Segel NH, Li QW, Zhu Y, et al. A novel multimarker assay for the phenotypic profiling of circulating tumor cells in hepatocellular carcinoma. Liver Transpl. 2018;24(7):946–60.PubMedPubMedCentralGoogle Scholar
  54. 54.
    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.PubMedGoogle Scholar
  55. 55.
    Lai HC, Yeh CC, Jeng LB, Huang SF, Liao PY, Lei FJ, et al. Androgen receptor mitigates postoperative disease progression of hepatocellular carcinoma by suppressing CD90+ populations and cell migration and by promoting anoikis in circulating tumor cells. Oncotarget. 2016;7(29):46448–65.PubMedPubMedCentralGoogle Scholar
  56. 56.
    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. 2016;7(3):2646–59.PubMedGoogle Scholar
  57. 57.
    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.PubMedGoogle Scholar
  58. 58.
    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.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Ogle LF, Orr JG, Willoughby CE, Hutton C, McPherson S, Plummer R, et al. Imagestream detection and characterisation of circulating tumour cells - a liquid biopsy for hepatocellular carcinoma? J Hepatol. 2016;65(2):305–13.PubMedGoogle Scholar
  60. 60.
    Ou H, Huang Y, Xiang L, Chen Z, Fang Y, Lin Y, et al. Circulating tumor cell phenotype indicates poor survival and recurrence after surgery for hepatocellular carcinoma. Dig Dis Sci. 2018;63(9):2373–80.PubMedGoogle Scholar
  61. 61.
    Qi LN, Xiang BD, Wu FX, Ye JZ, Zhong JH, Wang YY, et al. Circulating tumor cells undergoing EMT provide a metric for diagnosis and prognosis of patients with hepatocellular carcinoma. Cancer Res. 2018;78:4731–44.PubMedGoogle Scholar
  62. 62.
    Schulze K, Von Felden J, Krech T, Ewald F, Nashan B, Lohse AW, et al. EpCAM-positive circulating tumor cells as liquid biomarker for early micrometastases and HCC recurrence risk. J Hepatol. 2017;66(1):S457.Google Scholar
  63. 63.
    Shen J, Wang W, Zhu X, Ni C. EpCAM-positive circulating tumor cells independently predict poor outcomes of transcatheter arterial chemoembolization in patients with unresectable hepatocellular carcinoma. J Vasc Interv Radiol. 2018;29(4):S119.Google Scholar
  64. 64.
    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.PubMedGoogle Scholar
  65. 65.
    von Felden J, Schulze K, Krech T, Ewald F, Nashan B, Pantel K, et al. Circulating tumor cells as liquid biomarker for high HCC recurrence risk after curative liver resection. Oncotarget. 2017;8(52):89978–87.Google Scholar
  66. 66.
    Wang S, Zheng Y, Liu J, Huo F, Zhou J. Analysis of circulating tumor cells in patients with hepatocellular carcinoma recurrence following liver transplantation. J Investig Med. 2018;66(5):1–6.PubMedGoogle Scholar
  67. 67.
    Xue F, Shi S, Zhang Z, Xu C, Zheng J, Qin T, et al. Application of a novel liquid biopsy in patients with hepatocellular carcinoma undergoing liver transplantation. Oncol Lett. 2018;15(4):5481–8.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Zhou Y, Wang B, Wu J, Zhang C, Zhou Y, Yang X, et al. Association of preoperative EpCAM circulating tumor cells and peripheral Treg cell levels with early recurrence of hepatocellular carcinoma following radical hepatic resection. BMC Cancer. 2016;16:506.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Yin LC, Luo ZC, Gao YX, Li Y, Peng Q, Gao Y. Twist expression in circulating hepatocellular carcinoma cells predicts metastasis and prognoses. Biomed Res Int. 2018;2018:1–12.Google Scholar
  70. 70.
    Fang ZT, Zhang W, Wang GZ, Zhou B, Yang GW, Qu XD, et al. Circulating tumor cells in the central and peripheral venous compartment - assessing hematogenous dissemination after transarterial chemoembolization of hepatocellular carcinoma. OncoTargets Ther. 2014;7:1311–8.Google Scholar
  71. 71.
    Kelley RK, Lee MR, Hwang J, Gordan JD, Nimeiri HS, Bocobo AG, et al. Detection of circulating tumor cells (CTC) using a non-EpCAM-based, high-definition, single-cell assay in advanced hepatocellular carcinoma (HCC) for patients enrolled on phase I and II trials of sorafenib plus temsirolimus. J Clin Oncol. 2017;35:4.Google Scholar
  72. 72.
    Kelley RK, Magbanua MJM, 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(1):206.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Li P, Chen P, Peng X, Ma C, Zhang W, Dai X. HOXC6 predicts invasion and poor survival in hepatocellular carcinoma by driving epithelial-mesenchymal transition. Aging. 2018;10:2570–84.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Lee HM, Joh JW, Seo SR, Kim WT, Kim MK, Choi HS, et al. Cell-surface major vault protein promotes cancer progression through harboring mesenchymal and intermediate circulating tumor cells in hepatocellular carcinomas. Sci Rep. 2017;7(1):13201.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Wang Z, Luo L, Cheng Y, He G, Peng B, Gao Y, et al. Correlation between postoperative early recurrence of hepatocellular carcinoma and mesenchymal circulating tumor cells in peripheral blood. J Gastrointest Surg. 2018;22(4):633–9.PubMedGoogle Scholar
  77. 77.
    Gkountela S, Castro-Giner F, Szczerba BM, Vetter M, Landin J, Scherrer R, et al. Circulating tumor cell clustering shapes DNA methylation to enable metastasis seeding. Cell. 2019;176(1–2):98–112 e14.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Park S, Lee EJ, Rim CH, Seong J. Cell-free DNA as a predictive marker after radiation therapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2017;99(2):S89–90.Google Scholar
  79. 79.
    Park S, Lee EJ, Rim CH, Seong J. Plasma cell-free DNA as a predictive marker after radiotherapy for hepatocellular carcinoma. Yonsei Med J. 2018;59(4):470–9.PubMedPubMedCentralGoogle Scholar
  80. 80.
    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.PubMedGoogle Scholar
  81. 81.
    Kanekiyo S, Iizuka N, Tsunedomi R, Tokumitsu Y, Hashimoto N, Tokuhisa Y, et al. Preoperative serum methylation signature as prognostic tool after curative hepatectomy in patients with hepatocellular carcinoma. Anticancer Res. 2015;35(2):997–1007.PubMedGoogle Scholar
  82. 82.
    Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim D-W, et al. Alectinib versus Crizotinib in untreated ALK-positive non–small-cell lung cancer. N Engl J Med. 2017;377(9):829–38.PubMedGoogle Scholar
  83. 83.
    Diaz LA, Marabelle A, Delord J-P, Shapira-Frommer R, Geva R, Peled N, et al. Pembrolizumab therapy for microsatellite instability high (MSI-H) colorectal cancer (CRC) and non-CRC. J Clin Oncol. 2017;35(15_suppl):3071.Google Scholar
  84. 84.
    Llovet JM, Pena CE, Lathia CD, Shan M, Meinhardt G, Bruix J, et al. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2012;18(8):2290–300.PubMedGoogle Scholar
  85. 85.
    Teufel M, Köchert K, Meinhardt G, Bruix J. Efficacy of regorafenib (REG) in patients with hepatocellular carcinoma (HCC) in the phase III RESORCE trial according to alpha-fetoprotein (AFP) and c-Met levels as predictors of poor prognosis. J Clin Oncol. 2017;35(15_suppl):4078.Google Scholar
  86. 86.
    Zhu AX, Kang Y-K, Yen C-J, Finn RS, Galle PR, Llovet JM, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282–96.PubMedGoogle Scholar
  87. 87.
    Abou-Alfa GK, El-Khoueiry AB, Meyer T, Rimassa L, Merle P, Chan SL, et al., editors. Outcomes by baseline alpha-fetoprotein (AFP) levels in the phase 3 celestial trial of cabozantinib (C) versus placebo (P) in previously treated advanced hepatocellular carcinoma (HCC)2018: WILEY 111 RIVER ST, HOBOKEN 07030–5774, NJ USA.Google Scholar
  88. 88.
    Teufel M, Seidel H, Kochert K, Meinhardt G, Finn RS, Llovet JM, et al. Biomarkers associated with response to Regorafenib in patients with hepatocellular carcinoma. Gastroenterology. 2019;156(6):1731–41.PubMedGoogle Scholar
  89. 89.
    Szymańska K, Lesi OA, Kirk GD, Sam O, Taniere P, Scoazec J-Y, et al. Ser-249TP53 mutation in tumour and plasma DNA of hepatocellular carcinoma patients from a high incidence area in the Gambia, West Africa. Int J Cancer. 2004;110(3):374–9.PubMedGoogle Scholar
  90. 90.
    Wang J, Qin Y, Li B, Sun Z, Yang B. Detection of aberrant promoter methylation of GSTP1 in the tumor and serum of Chinese human primary hepatocellular carcinoma patients. Clin Biochem. 2006;39(4):344–8.PubMedGoogle Scholar
  91. 91.
    Howell J, Atkinson SR, Pinato DJ, Knapp S, Ward C, Minisini R, et al. Identification of mutations in circulating cell-free tumour DNA as a biomarker in hepatocellular carcinoma. Eur J Cancer. 2019;116:56–66.PubMedGoogle Scholar
  92. 92.
    Riviere P, Fanta PT, Ikeda S, Baumgartner J, Heestand GM, Kurzrock R. The mutational landscape of gastrointestinal malignancies as reflected by circulating tumor DNA. Mol Cancer Ther. 2018;17(1):297–305.PubMedGoogle Scholar
  93. 93.
    Miyamoto DT, Zheng Y, Wittner BS, Lee RJ, Zhu H, Broderick KT, et al. RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science. 2015;349(6254):1351–6.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Lohr JG, Kim S, Gould J, Knoechel B, Drier Y, Cotton MJ, et al. Genetic interrogation of circulating multiple myeloma cells at single-cell resolution. Sci Transl Med. 2016;8(363):–363ra147.PubMedPubMedCentralGoogle Scholar
  95. 95.
    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.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Park SR, Oh CR, Kong SY, Kim MK, Yoon KA, Cho EH, et al. Biomarker analysis in circulating cell-free DNA in patients treated with sorafenib for advanced hepatocellular carcinoma. Cancer Res. 2018;78:13.Google Scholar
  97. 97.
    Wyatt AW, Azad AA, Volik SV, Annala M, Beja K, McConeghy B, et al. Genomic alterations in cell-free DNA and enzalutamide resistance in castration-resistant prostate cancer. JAMA Oncol. 2016;2(12):1598–606.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Garcia-Murillas I, Schiavon G, Weigelt B, Ng C, Hrebien S, Cutts RJ, et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med. 2015;7(302):302ra133.PubMedGoogle Scholar
  99. 99.
    Smerage JB, Barlow WE, Hortobagyi GN, Winer EP, Leyland-Jones B, Srkalovic G, et al. Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol. 2014;32(31):3483–9.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Gastroenterology and Hepatology, Department of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborUSA

Personalised recommendations