Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Clinical implementation and current advancement of blood liquid biopsy in cancer

Journal of Human Genetics volume 66, pages 909–926 (2021)Cite this article

Subjects

Abstract

Liquid biopsies have been receiving tremendous attentions as easy, rapid, and non-invasive tools for cancer diagnosis. Liquid biopsy can be performed repeatedly for disease monitoring and is expected to overcome the limitations of tissue biopsies. With the advancement of next generation sequencing technologies, it is now possible to detect minute amount of tumor-derived circulation tumor DNA (ctDNA) from blood samples. Importantly, ctDNA detection could be complementary to tissue biopsies or tumor biomarkers particularly in cases of which tumor biopsy is clinically difficult to obtain. Here, we introduce the up-to-date technologies used in cfDNA-based liquid biopsy and review the clinical utilities of ctDNA in cancer screening, detection of minimal residual diseases, selection of molecular-targeted drugs, as well as monitoring of treatment responsiveness. We also discuss the challenges and future perspectives of liquid biopsy implementation in clinical setting.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Joosse SA, Pantel K. Tumor-educated platelets as liquid biopsy in cancer patients. Cancer Cell. 2015;28:552–4.

    Article  CAS  PubMed  Google Scholar 

  2. Thierry AR, El Messaoudi S, Gahan PB, Anker P, Stroun M. Origins, structures, and functions of circulating DNA in oncology. Cancer Metastasis Rev. 2016;35:347–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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 USA. 2015;112:E1317–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Underhill HR, Kitzman JO, Hellwig S, Welker NC, Daza R, Baker DN, et al. Fragment length of circulating tumor DNA. PLoS Genet. 2016;12:e1006162.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6:224ra24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Yao W, Mei C, Nan X, Hui L. Evaluation and comparison of in vitro degradation kinetics of DNA in serum, urine and saliva: a qualitative study. Gene. 2016;590:142–8.

    Article  CAS  PubMed  Google Scholar 

  7. Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14:985–90.

    Article  CAS  PubMed  Google Scholar 

  8. Corcoran RB, Chabner BA. Application of cell-free DNA analysis to cancer treatment. N Engl J Med. 2018;379:1754–65.

    Article  CAS  PubMed  Google Scholar 

  9. García-Foncillas J, Alba E, Aranda E, Díaz-Rubio E, López-López R, Tabernero J, et al. Incorporating BEAMing technology as a liquid biopsy into clinical practice for the management of colorectal cancer patients: an expert taskforce review. Ann Oncol. 2017;28:2943–9.

    Article  PubMed  PubMed Central  Google Scholar 

  10. García-Saenz JA, Ayllón P, Laig M, Acosta-Eyzaguirre D, García-Esquinas M, Montes M, et al. Tumor burden monitoring using cell-free tumor DNA could be limited by tumor heterogeneity in advanced breast cancer and should be evaluated together with radiographic imaging. BMC Cancer. 2017;17:210.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Sausen M, Phallen J, Adleff V, Jones S, Leary RJ, Barrett MT, et al. Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients. Nat Commun. 2015;6:7686.

    Article  PubMed  Google Scholar 

  12. Olsson E, Winter C, George A, Chen Y, Howlin J, Tang MH, et al. Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO Mol Med. 2015;7:1034–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tie J, Cohen JD, Wang Y, Christie M, Simons K, Lee M, et al. Circulating tumor DNA analyses as markers of recurrence risk and benefit of adjuvant therapy for stage III colon cancer. JAMA Oncol. 2019;5:1710–7.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Peng M, Xie Y, Li X, Qian Y, Tu X, Yao X, et al. Resectable lung lesions malignancy assessment and cancer detection by ultra-deep sequencing of targeted gene mutations in plasma cell-free DNA. J Med Genet. 2019;56:647–53.

    Article  CAS  PubMed  Google Scholar 

  15. Shendure J, Ji H. Next-generation DNA sequencing. Nat Biotechnol. 2008;26:1135–45.

    Article  CAS  PubMed  Google Scholar 

  16. Chin YM, Takahashi Y, Chan HT, Otaki M, Fujishima M, Shibayama T, et al. Ultradeep targeted sequencing of circulating tumor DNA in plasma of early and advanced breast cancer. Cancer Sci. 2020;112:454–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer. 2017;17:223–38.

    Article  CAS  PubMed  Google Scholar 

  18. Chan HT, Nagayama S, Chin YM, Otaki M, Hayashi R, Kiyotani K, et al. Clinical significance of clonal hematopoiesis in the interpretation of blood liquid biopsy. Mol Oncol 2020;14:1719–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kukita Y, Matoba R, Uchida J, Hamakawa T, Doki Y, Imamura F, et al. High-fidelity target sequencing of individual molecules identified using barcode sequences: de novo detection and absolute quantitation of mutations in plasma cell-free DNA from cancer patients. DNA Res 2015;22:269–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Schmitt MW, Kennedy SR, Salk JJ, Fox EJ, Hiatt JB, Loeb LA. Detection of ultra-rare mutations by next-generation sequencing. Proc Natl Acad Sci USA. 2012;109:14508–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bar DZ, Arlt MF, Brazier JF, Norris WE, Campbell SE, Chines P, et al. A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome. J Med Genet 2017;54:212–16.

    Article  CAS  PubMed  Google Scholar 

  22. Newman AM, Lovejoy AF, Klass DM, Kurtz DM, Chabon JJ, Scherer F, et al. Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol. 2016;34:547–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Newman AM, Bratman SV, To J, Wynne JF, Eclov NC, Modlin LA, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20:548–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kinde I, Wu J, Papadopoulos N, Kinzler KW, Vogelstein B. Detection and quantification of rare mutations with massively parallel sequencing. Proc Natl Acad Sci USA. 2011;108:9530–5.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Adalsteinsson VA, Ha G, Freeman SS, Choudhury AD, Stover DG, Parsons HA, et al. Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors. Nat Commun. 2017;8:1324.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Hemming ML, Klega KS, Rhoades J, Ha G, Acker KE, Andersen JL, et al. Detection of circulating tumor DNA in patients with leiomyosarcoma with progressive disease. JCO Precis Oncol. 2019;2019:PO.18.00235.

    Google Scholar 

  27. Zviran A, Schulman RC, Shah M, Hill STK, Deochand S, Khamnei CC, et al. Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring. Nat Med. 2020;26:1114–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Han DSC, Ni M, Chan RWY, Chan VWH, Lui KO, Chiu RWK, et al. The biology of cell-free DNA fragmentation and the roles of DNASE1, DNASE1L3, and DFFB. Am J Hum Genet. 2020;106:202–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sun K, Jiang P, Cheng SH, Cheng THT, Wong J, Wong VWS, et al. Orientation-aware plasma cell-free DNA fragmentation analysis in open chromatin regions informs tissue of origin. Genome Res. 2019;29:418–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cristiano S, Leal A, Phallen J, Fiksel J, Adleff V, Bruhm DC, et al. Genome-wide cell-free DNA fragmentation in patients with cancer. Nature. 2019;570:385–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Moss J, Magenheim J, Neiman D, Zemmour H, Loyfer N, Korach A, et al. Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease. Nat Commun. 2018;9:5068.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Li W, Li Q, Kang S, Same M, Zhou Y, Sun C, et al. CancerDetector: ultrasensitive and non-invasive cancer detection at the resolution of individual reads using cell-free DNA methylation sequencing data. Nucleic Acids Res. 2018;46:e89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Brancaccio M, Natale F, Falco G, Angrisano T. Cell-free DNA methylation: the new frontiers of pancreatic cancer biomarkers’ discovery. Genes (Basel). 2019;11:14.

    Article  CAS  Google Scholar 

  34. Liang TJ, Wang HX, Zheng YY, Cao YQ, Wu X, Zhou X, et al. APC hypermethylation for early diagnosis of colorectal cancer: a meta-analysis and literature review. Oncotarget 2017;8:46468–79.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Hulbert A, Jusue-Torres I, Stark A, Chen C, Rodgers K, Lee B, et al. Early detection of lung cancer using DNA promoter hypermethylation in plasma and sputum. Clin Cancer Res. 2017;23:1998–2005.

    Article  CAS  PubMed  Google Scholar 

  36. Uehiro N, Sato F, Pu F, Tanaka S, Kawashima M, Kawaguchi K, et al. Circulating cell-free DNA-based epigenetic assay can detect early breast cancer. Breast Cancer Res. 2016;18:129.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Constancio V, Nunes SP, Henrique R, Jeronimo C. DNA Methylation-based testing in liquid biopsies as detection and prognostic biomarkers for the four major cancer types. Cells. 2020;9:624.

    Article  CAS  PubMed Central  Google Scholar 

  38. Vrba L, Oshiro MM, Kim SS, Garland LL, Placencia C, Mahadevan D, et al. DNA methylation biomarkers discovered in silico detect cancer in liquid biopsies from non-small cell lung cancer patients. Epigenetics. 2020;15:419–30.

    Article  PubMed  Google Scholar 

  39. Constancio V, Nunes SP, Moreira-Barbosa C, Freitas R, Oliveira J, Pousa I, et al. Early detection of the major male cancer types in blood-based liquid biopsies using a DNA methylation panel. Clin Epigenetics. 2019;11:175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shen SY, Singhania R, Fehringer G, Chakravarthy A, Roehrl MHA, Chadwick D, et al. Sensitive tumour detection and classification using plasma cell-free DNA methylomes. Nature. 2018;563:579–83.

    Article  CAS  PubMed  Google Scholar 

  41. Shen SY, Burgener JM, Bratman SV, De, Carvalho DD. Preparation of cfMeDIP-seq libraries for methylome profiling of plasma cell-free DNA. Nat Protoc. 2019;14:2749–80.

    Article  CAS  PubMed  Google Scholar 

  42. Duffy MJ, Evoy D, McDermott EW. CA 15-3: uses and limitation as a biomarker for breast cancer. Clin Chim Acta. 2010;411:1869–74.

    Article  CAS  PubMed  Google Scholar 

  43. Luo G, Jin K, Deng S, Cheng H, Fan Z, Gong Y, et al. Roles of CA19-9 in pancreatic cancer: biomarker, predictor and promoter. Biochim Biophys Acta Rev Cancer. 2020;1875:188409.

    Article  PubMed  CAS  Google Scholar 

  44. Nikolaou S, Qiu S, Fiorentino F, Rasheed S, Tekkis P, Kontovounisios C. Systematic review of blood diagnostic markers in colorectal cancer. Tech Coloproctol. 2018;22:481–98.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Matulonis UA, Sood AK, Fallowfield L, Howitt BE, Sehouli J, Karlan BY. Ovarian cancer. Nat Rev Dis Prim. 2016;2:16061.

    Article  PubMed  Google Scholar 

  46. Wu D, Ni J, Beretov J, Cozzi P, Willcox M, Wasinger V, et al. Urinary biomarkers in prostate cancer detection and monitoring progression. Crit Rev Oncol Hematol. 2017;118:15–26.

    Article  PubMed  Google Scholar 

  47. Young GP, Pedersen SK, Mansfield S, Murray DH, Baker RT, Rabbitt P, et al. A cross-sectional study comparing a blood test for methylated BCAT1 and IKZF1 tumor-derived DNA with CEA for detection of recurrent colorectal cancer. Cancer Med. 2016;5:2763–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Coombes RC, Page K, Salari R, Hastings RK, Armstrong A, Ahmed S, et al. Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence. Clin Cancer Res. 2019;25:4255–63.

    Article  CAS  PubMed  Google Scholar 

  49. Pairawan S, Hess KR, Janku F, Sanchez NS, Mills Shaw KR, Eng C, et al. Cell-free circulating tumor DNA variant allele frequency associates with survival in metastatic cancer. Clin Cancer Res 2020;26:1924–31.

    Article  CAS  PubMed  Google Scholar 

  50. Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature 2017;545:446–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tie J, Wang Y, Tomasetti C, Li L, Springer S, Kinde I, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med. 2016;8:346ra92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Jiang J, Ye S, Xu Y, Chang L, Hu X, Ru G, et al. Circulating tumor DNA as a potential marker to detect minimal residual disease and predict recurrence in pancreatic cancer. Front Oncol. 2020;10:1220.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Chaudhuri AA, Chabon JJ, Lovejoy AF, Newman AM, Stehr H, Azad TD, et al. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Disco. 2017;7:1394–403.

    Article  CAS  Google Scholar 

  54. Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007;370:2020–9.

    Article  PubMed  Google Scholar 

  55. Yang J, Gong Y, Lam VK, Shi Y, Guan Y, Zhang Y, et al. Deep sequencing of circulating tumor DNA detects molecular residual disease and predicts recurrence in gastric cancer. Cell Death Dis. 2020;11:346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Christensen E, Birkenkamp-Demtröder K, Sethi H, Shchegrova S, Salari R, Nordentoft I, et al. Early detection of metastatic relapse and monitoring of therapeutic efficacy by ultra-deep sequencing of plasma cell-free DNA in patients with urothelial bladder carcinoma. J Clin Oncol. 2019;37:1547–57.

    Article  CAS  PubMed  Google Scholar 

  57. Young AL, Challen GA, Birmann BM, Druley TE. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat Commun. 2016;7:12484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Tie J, Cohen JD, Lo SN, Wang Y, Li L, Christie M, et al. Prognostic significance of postsurgery circulating tumor DNA in nonmetastatic colorectal cancer: individual patient pooled analysis of three cohort studies. Int J Cancer. 2021;148:1014–26.

    Article  CAS  PubMed  Google Scholar 

  59. McDonald BR, Contente-Cuomo T, Sammut SJ, Odenheimer-Bergman A, Ernst B, Perdigones N, et al. Personalized circulating tumor DNA analysis to detect residual disease after neoadjuvant therapy in breast cancer. Sci Transl Med. 2019;11:eaax7392.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368:1199–209.

    Article  CAS  PubMed  Google Scholar 

  61. Birkenkamp-Demtröder K, Christensen E, Nordentoft I, Knudsen M, Taber A, Høyer S, et al. Monitoring treatment response and metastatic relapse in advanced bladder cancer by liquid biopsy analysis. Eur Urol. 2018;73:535–40.

    Article  PubMed  Google Scholar 

  62. Siravegna G, Lazzari L, Crisafulli G, Sartore-Bianchi A, Mussolin B, Cassingena A, et al. Radiologic and genomic evolution of individual metastases during HER2 blockade in colorectal cancer. Cancer Cell. 2018;34:148–62, e7.

    Article  CAS  PubMed  Google Scholar 

  63. Hrebien S, Citi V, Garcia-Murillas I, Cutts R, Fenwick K, Kozarewa I, et al. Early ctDNA dynamics as a surrogate for progression-free survival in advanced breast cancer in the BEECH trial. Ann Oncol. 2019;30:945–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Annala M, Struss WJ, Warner EW, Beja K, Vandekerkhove G, Wong A, et al. Treatment outcomes and tumor loss of heterozygosity in germline DNA repair-deficient prostate cancer. Eur Urol. 2017;72:34–42.

    Article  CAS  PubMed  Google Scholar 

  65. Lallous N, Volik SV, Awrey S, Leblanc E, Tse R, Murillo J, et al. Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients. Genome Biol. 2016;17:10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Conteduca V, Wetterskog D, Sharabiani MTA, Grande E, Fernandez-Perez MP, Jayaram A, et al. Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study. Ann Oncol. 2017;28:1508–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Watanabe F, Suzuki K, Tamaki S, Abe I, Endo Y, Takayama Y, et al. Longitudinal monitoring of KRAS-mutated circulating tumor DNA enables the prediction of prognosis and therapeutic responses in patients with pancreatic cancer. PLoS One. 2019;14:e0227366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 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;7:302ra133.

    Article  PubMed  Google Scholar 

  69. Azad TD, Chaudhuri AA, Fang P, Qiao Y, Esfahani MS, Chabon JJ, et al. Circulating tumor DNA analysis for detection of minimal residual disease after chemoradiotherapy for localized esophageal cancer. Gastroenterology. 2020;158:494–505, e6.

    Article  CAS  PubMed  Google Scholar 

  70. Low SK, Nakamura Y. The road map of cancer precision medicine with the innovation of advanced cancer detection technology and personalized immunotherapy. Jpn J Clin Oncol. 2019;49:596–603.

    Article  PubMed  Google Scholar 

  71. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786–92.

    Article  CAS  PubMed  Google Scholar 

  73. Wang Z, Chen R, Wang S, Zhong J, Wu M, Zhao J, et al. Quantification and dynamic monitoring of EGFR T790M in plasma cell-free DNA by digital PCR for prognosis of EGFR-TKI treatment in advanced NSCLC. PLoS One. 2014;9:e110780.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Schiavon G, Hrebien S, Garcia-Murillas I, Cutts RJ, Pearson A, Tarazona N, et al. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med. 2015;7:313ra182.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Nakamura Y, Taniguchi H, Ikeda M, Bando H, Kato K, Morizane C, et al. Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies. Nat Med. 2020;26:1859–64.

    Article  CAS  PubMed  Google Scholar 

  76. Turner NC, Kingston B, Kilburn LS, Kernaghan S, Wardley AM, Macpherson IR, et al. Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial. Lancet Oncol. 2020;21:1296–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rothwell DG, Ayub M, Cook N, Thistlethwaite F, Carter L, Dean E, et al. Utility of ctDNA to support patient selection for early phase clinical trials: the TARGET study. Nat Med. 2019;25:738–43.

    Article  CAS  PubMed  Google Scholar 

  78. Chan KCA, Woo JKS, King A, Zee BCY, Lam WKJ, Chan SL, et al. Analysis of Plasma Epstein-Barr Virus DNA to Screen for Nasopharyngeal Cancer. N Engl J Med. 2017;377:513–22.

    Article  CAS  PubMed  Google Scholar 

  79. Xie SH, Yu IT, Tse LA, Au JS, Lau JS. Tobacco smoking, family history, and the risk of nasopharyngeal carcinoma: a case-referent study in Hong Kong Chinese. Cancer Causes Control. 2015;26:913–21.

    Article  PubMed  Google Scholar 

  80. Cohen JD, Li L, Wang Y, Thoburn C, Afsari B, Danilova L, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018;359:926–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lennon AM, Buchanan AH, Kinde I, Warren A, Honushefsky A, Cohain AT, et al. Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention. Science. 2020;369:eabb9601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Liu MC, Oxnard GR, Klein EA, Swanton C, Seiden MV, Cummings SR, et al. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol. 2020;31:745–59.

    Article  CAS  PubMed  Google Scholar 

  83. Pittella-Silva F, Chin YM, Chan HT, Nagayama S, Miyauchi E, Low SK, et al. Plasma or serum: which is preferable for mutation detection in liquid biopsy? Clin Chem. 2020;66:946–57.

    Article  PubMed  Google Scholar 

  84. Alidousty C, Brandes D, Heydt C, Wagener S, Wittersheim M, Schäfer SC, et al. Comparison of blood collection tubes from three different manufacturers for the collection of cell-free DNA for liquid biopsy mutation testing. J Mol Diagn. 2017;19:801–4.

    Article  CAS  PubMed  Google Scholar 

  85. Kang Q, Henry NL, Paoletti C, Jiang H, Vats P, Chinnaiyan AM, et al. Comparative analysis of circulating tumor DNA stability In K(3)EDTA, Streck, and CellSave blood collection tubes. Clin Biochem. 2016;49:1354–60.

    Article  CAS  PubMed  Google Scholar 

  86. Razavi P, Li BT, Brown DN, Jung B, Hubbell E, Shen R, et al. High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants. Nat Med. 2019;25:1928–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488–98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Jaiswal S, Ebert BL. Clonal hematopoiesis in human aging and disease. Science. 2019;366:eaan4673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Zink F, Stacey SN, Norddahl GL, Frigge ML, Magnusson OT, Jonsdottir I, et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood. 2017;130:742–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Genovese G, Kähler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371:2477–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Hu Y, Ulrich BC, Supplee J, Kuang Y, Lizotte PH, Feeney NB, et al. False-positive plasma genotyping due to clonal hematopoiesis. Clin Cancer Res. 2018;24:4437–43.

    Article  CAS  PubMed  Google Scholar 

  92. Leal A, van Grieken NCT, Palsgrove DN, Phallen J, Medina JE, Hruban C, et al. White blood cell and cell-free DNA analyses for detection of residual disease in gastric cancer. Nat Commun. 2020;11:525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. McKerrell T, Park N, Moreno T, Grove CS, Ponstingl H, Stephens J, et al. Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep. 2015;10:1239–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Liu J, Chen X, Wang J, Zhou S, Wang CL, Ye MZ, et al. Biological background of the genomic variations of cf-DNA in healthy individuals. Ann Oncol. 2019;30:464–70.

    Article  CAS  PubMed  Google Scholar 

  95. Xia L, Li Z, Zhou B, Tian G, Zeng L, Dai H, et al. Statistical analysis of mutant allele frequency level of circulating cell-free DNA and blood cells in healthy individuals. Sci Rep. 2017;7:7526.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Chan HT, Chin YM, Nakamura Y, Low SK. Clonal hematopoiesis in liquid biopsy: from biological noise to valuable clinical implications. Cancers (Basel). 2020;12:2277.

    Article  CAS  Google Scholar 

  97. Wang Y, Springer S, Mulvey CL, Silliman N, Schaefer J, Sausen M, et al. Detection of somatic mutations and HPV in the saliva and plasma of patients with head and neck squamous cell carcinomas. Sci Transl Med. 2015;7:293ra104.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Springer SU, Chen CH, Rodriguez Pena MDC, Li L, Douville C, Wang Y, et al. Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy. Elife. 2018;7:e32143.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Hirotsu Y, Yokoyama H, Amemiya K, Hagimoto T, Daimon H, Hosaka K, et al. Genomic profile of urine has high diagnostic sensitivity compared to cytology in non-invasive urothelial bladder cancer. Cancer Sci. 2019;110:3235–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370:1287–97.

    Article  CAS  PubMed  Google Scholar 

  101. Wang Y, Li L, Douville C, Cohen JD, Yen TT, Kinde I, et al. Evaluation of liquid from the Papanicolaou test and other liquid biopsies for the detection of endometrial and ovarian cancers. Sci Transl Med. 2018;10:eaap8793.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. De Mattos-Arruda L, Mayor R, Ng CKY, Weigelt B, Martínez-Ricarte F, Torrejon D, et al. Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma. Nat Commun. 2015;6:8839.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Pentsova EI, Shah RH, Tang J, Boire A, You D, Briggs S, et al. Evaluating cancer of the central nervous system through next-generation sequencing of cerebrospinal fluid. J Clin Oncol. 2016;34:2404–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Escudero L, Llort A, Arias A, Diaz-Navarro A, Martínez-Ricarte F, Rubio-Perez C, et al. Circulating tumour DNA from the cerebrospinal fluid allows the characterisation and monitoring of medulloblastoma. Nat Commun. 2020;11:5376.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Kinde I, Papadopoulos N, Kinzler KW, Vogelstein B. FAST-SeqS: a simple and efficient method for the detection of aneuploidy by massively parallel sequencing. PLoS One. 2012;7:e41162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Pan W, Gu W, Nagpal S, Gephart MH, Quake SR. Brain tumor mutations detected in cerebral spinal fluid. Clin Chem. 2015;61:514–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Krug AK, Enderle D, Karlovich C, Priewasser T, Bentink S, Spiel A, et al. Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma. Ann Oncol. 2018;29:700–6.

    Article  CAS  PubMed  Google Scholar 

  108. Best MG, Sol N, Kooi I, Tannous J, Westerman BA, Rustenburg F, et al. RNA-Seq of tumor-educated platelets enables blood-based pan-cancer, multiclass, and molecular pathway cancer diagnostics. Cancer Cell. 2015;28:666–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan

    Kazunori Watanabe, Yusuke Nakamura & Siew-Kee Low

  2. Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan

    Kazunori Watanabe

Authors
  1. Kazunori Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yusuke Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Siew-Kee Low
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Siew-Kee Low.

Ethics declarations

Conflict of interest

YN is a stockholder and a scientific advisor of OncoTherapy Science, Inc. S-KL is a scientific advisor of Cancer Precision Medicine, Inc. This study is unrelated to the activity in these companies.

Additional information

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Watanabe, K., Nakamura, Y. & Low, SK. Clinical implementation and current advancement of blood liquid biopsy in cancer. J Hum Genet 66, 909–926 (2021). https://doi.org/10.1038/s10038-021-00939-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s10038-021-00939-5

Search

Advanced search

Quick links