The dawn of the liquid biopsy in the fight against cancer

Irma G Domínguez-Vigil, Ana K Moreno-Martínez, Julia Y Wang, Michael H A Roehrl, Hugo A Barrera-Saldaña, Irma G Domínguez-Vigil, Ana K Moreno-Martínez, Julia Y Wang, Michael H A Roehrl, Hugo A Barrera-Saldaña

Abstract

Cancer is a molecular disease associated with alterations in the genome, which, thanks to the highly improved sensitivity of mutation detection techniques, can be identified in cell-free DNA (cfDNA) circulating in blood, a method also called liquid biopsy. This is a non-invasive alternative to surgical biopsy and has the potential of revealing the molecular signature of tumors to aid in the individualization of treatments. In this review, we focus on cfDNA analysis, its advantages, and clinical applications employing genomic tools (NGS and dPCR) particularly in the field of oncology, and highlight its valuable contributions to early detection, prognosis, and prediction of treatment response.

Keywords: cfDNA; ctDNA; diagnostics; early detection; liquid biopsy.

Conflict of interest statement

CONFLICT OF INTEREST The authors have no disclosures.

Figures

Figure 1. Timeline of liquid biopsy development
Figure 1. Timeline of liquid biopsy development
Figure 2. Number of publications per year…
Figure 2. Number of publications per year in PubMed, using the terms “liquid biopsy”, “cell free DNA”, “circulating tumor DNA”, “exosomes”, “micro RNA”, and “circulating tumor cells” as of July 1, 2017
Figure 3
Figure 3
Comparison of features between surgical (tissue-based) and liquid biopsies (left) and overview of the various elements of the liquid biopsy workflow (A-F, right).

References

    1. National Cancer Institute . Definition of liquid biopsy - NCI Dictionary of Cancer Terms. National Cancer Institute;
    1. Mandel P, Metais P. [Les acides nucléiques du plasma sanguin chez l’homme]. [Article in French] C R Seances Soc Biol Fil. 1948;142:241–3.
    1. McLarty JL, Yeh CH. Circulating cell-free DNA: The blood biopsy in cancer management. Cell Sci Rep. 2015;2:00021.
    1. Cell-free DNA screening for fetal aneuploidy Obs Gynecol. 2015;126:e31–e37.
    1. Osborne CM, Hardisty E, Devers P, Kaiser-Rogers K, Hayden MA, Goodnight W, Vora NL. Discordant noninvasive prenatal testing results in a patient subsequently diagnosed with metastatic disease. Prenat Diagn. 2013;33:609–11.
    1. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 2009;458:719–24.
    1. Russo A, Rolfo C, Passigliia F, Rosell R. Targeted Therapies for Non-Small Cell Lung Cancer. In: Russo A, Rosell R, Rolfo C, editors. Targeted Therapies for Solid Tumors: A Handbook for Moving Toward New Frontiers in Cancer Treatment. New York: Humana Press; 2015. pp. 89–101.
    1. Meldrum C, Doyle MA, Tothill RW. Next-Generation Sequencing for Cancer Diagnostics: a Practical Perspective. Clin Biochem Rev. 2011;32:177–95.
    1. The Cancer Genome Atlas Research Network Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061–8.
    1. The Cancer Genome Atlas Research Network Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–15.
    1. The Cancer Genome Atlas Research Network Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67–73.
    1. The Cancer Genome Atlas Research Network Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543–50.
    1. Chin EL, da Silva C, Hegde M. Assessment of clinical analytical sensitivity and specificity of next-generation sequencing for detection of simple and complex mutations. BMC Genet. 2013;14:6.
    1. Ko J, Carpenter E, Issadore D. Detection and isolation of circulating exosomes and microvesicles for cancer monitoring and diagnostics using micro-/nano-based devices. Analyst. 2015;141:450–60.
    1. Kerick M, Isau M, Timmermann B, Sültmann H, Herwig R, Krobitsch S, Schaefer G, Verdorfer I, Bartsch G, Klocker H, Lehrach H, Schweiger R. Targeted high throughput sequencing in clinical cancer Settings: formaldehyde fixed-paraffin embedded (FFPE) tumor tissues, input amount and tumor heterogeneity. BMC Med Genomics. 2011;4:68.
    1. Cree IA. Liquid biopsy for cancer patients: Principles and practice. Pathogenesis. 2015;2:1–4.
    1. Heitzer E, Ulz P, Geigl JB. Circulating tumor DNA as a liquid biopsy for cancer. Clin Chem. 2015;61:112–23.
    1. Lewis AR, Valle JW, McNamara MG. Pancreatic cancer: Are “liquid biopsies” ready for prime-time? World J Gastroenterol. 2016;22:7175–85.
    1. Rolfo C, Castiglia M, Hong D, Alessandro R, Mertens I, Baggerman G, Zwaenepoel K, Gil-Bazo I, Passiglia F, Carreca AP, Taverna S, Vento R, Santini D, et al. Liquid biopsies in lung cancer: The new ambrosia of researchers. Biochim Biophys Acta. 2014;1846:539–46.
    1. Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: Monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10:472–84.
    1. Diaz LA, Bardelli A. Liquid biopsies: Genotyping circulating tumor DNA. Journal of Clinical Oncology. 2014;32:579–86.
    1. Wan JC, Massie C, Garcia-Corbacho J, James D, Caldas C, Pacey S, Baird R, Rosenfeld N. Liquid biopsies come of age: Towards implementation of circulating tumour DNA. Nat Rev Cancer. 2017;17:223–38.
    1. Zheng D, Ye X, Zhang MZ, Sun Y, Wang JY, Ni J, Zhang HP, Zhang L, Luo J, Zhang J, Tang L, Su B, Chen G, et al. Plasma EGFR T790M ctDNA status is associated with clinical outcome in advanced NSCLC patients with acquired EGFR-TKI resistance. Sci Rep. 2016;6:20913.
    1. Novello S, Barlesi F, Califano R, Cufer T, Ekman S, Levra MG, Kerr K, Popat S, Reck M, Senan S, Simo GV, Vansteenkiste J, Peters S. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(Suppl 5):v1–v27.
    1. Stroun M, Maurice P, Vasioukhin V, Lyautey J, Lederrey C, Lefort F, Rossier A, Chen XQ, Anker P. The origin and mechanism of circulating DNA. Ann NY Acad Sci. 2000;906:161–8.
    1. Alix-Panabières C, Pantel K. Clinical applications of circulating tumor cells and circulating tumor DNA as liquid biopsy. Cancer Discov. 2016;6:479–91.
    1. Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11:426–37.
    1. Cheng F, Su L, Qian C. Circulating tumor DNA: a promising biomarker in the liquid biopsy of cancer. Oncotarget. 2016;7:48832–41. .
    1. Li J, Dittmar RL, Xia S, Zhang H, Du M, Huang CC, Druliner BR, Boardman L, Wang L. Cell-free DNA copy number variations in plasma from colorectal cancer patients. Mol Oncol. 2017;11:1099–111.
    1. Soave A, Chun FK, Hillebrand T, Rink M, Weisbach L, Steinbach B, Fisch M, Pantel K, Schwarzenbach H. Copy number variations of circulating, cell-free DNA in urothelial carcinoma of the bladder patients treated with radical cystectomy: A prospective study. Oncotarget. 2017;8:56398–407. .
    1. Husain H, Nykin D, Bui N, Quan D, Gomez G, Woodward B, Venkatapathy S, Duttagupta R, Fung E, Lippman SM, Kurzrock R. Cell-free DNA from ascites and pleural effusions: Molecular insights into genomic aberrations and disease biology. Mol Cancer Ther. 2017;16:948–55.
    1. Li Z, Guo X, Tang L, Peng L, Chen M, Luo X, Wang S, Xiao Z, Deng Z, Dai L, Xia K, Wang J. Methylation analysis of plasma cell-free DNA for breast cancer early detection using bisulfite next-generation sequencing. Tumour Biol. 2016;37:13111–9.
    1. Fleischhacker M, Schmidt B. Circulating nucleic acids (CNAs) and cancer-A survey. Biochim Biophys Acta. 2007;1775:181–232.
    1. Siravegna G, Bardelli A. Genotyping cell-free tumor DNA in the blood to detect residual disease and drug resistance. Genome Biol. 2014;15:449.
    1. Diehl F, Li M, Dressman D, He Y, Shen D, Szabo S, Diaz LA, Jr, Goodman SN, David KA, Juhl H, Kinzler KW, Vogelstein B. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci U S A. 2005;102:16368–73.
    1. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6:224ra24.
    1. Ashworth TR. A case of cancer in which cells similar to those in the tumors were seen in the blood after death. The Australian Medical Journal. 1869;14:146–9.
    1. Lianidou ES, Strati A, Markou A. Circulating tumor cells as promising novel biomarkers in solid cancers. Crit Rev Clin Lab Sci. 2014;51:160–71.
    1. Pantel K, Alix-Panabières C. Detection methods of circulating tumor cells. J Thorac Dis. 2012;4:446–7.
    1. Park Y, Kitahara T, Urita T, Yoshida Y, Kato R. Expected clinical applications of circulating tumor cells in breast cancer. World J Clin Oncol. 2011;2:303–10.
    1. CellSearch CellSearch Circulating Tumor Cell Kit (Epithelial) User's Guide. 2013.
    1. Brock G, Castellanos-Rizaldos E, Hu L, Coticchia C, Skog J. Liquid biopsy for cancer screening, patient stratification and monitoring. Transl Cancer Res. 2015;4:280–90.
    1. Pantel K, Alix-Panabières C. Cell lines from circulating tumor cells. Oncoscience. 2015;2:1–2. .
    1. Kolostova K, Spicka J, Matkowski R, Bobek V. Isolation, primary culture, morphological and molecular characterization of circulating tumor cells in gynecological cancers. Am J Transl Res. 2015;7:1203–13.
    1. Kolostova K, Zhang Y, Hoffman RM, Bobek V. In vitro culture and characterization of human lung cancer circulating tumor cells isolated by size exclusion from an orthotopic nude-mouse model expressing fluorescent protein. J Fluoresc. 2014;24:1531–6.
    1. Maheswaran S, Haber DA. Ex vivo culture of CTCs: An emerging resource to guide cancer therapy. Cancer Res. 2015;75:2411–5.
    1. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.
    1. Lin J, Li J, Huang B, Liu J, Chen X, Chen XM, Xu YM, Huang LF, Wang XZ. Exosomes: Novel Biomarkers for Clinical Diagnosis. Sci World J. 2015;2015:657086.
    1. Sheridan C. Exosome cancer diagnostic reaches market. Nat Biotechnol. 2016;34:359–60.
    1. Vanni I, Alama A, Grossi F, Dal Bello MG, Coco S. Exosomes: A new horizon in lung cancer. Drug Discov Today. 2017;22:927–36.
    1. Witwer KW, Buzás EI, Bemis LT, Bora A, Lässer C, Lötvall J, Nolte-'t Hoen EN, Piper MG, Sivaraman S, Skog J, Théry C, Wauben MH, Hochberg F. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles. 2013;2:20360.
    1. Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, LeBleu VS, Mittendorf EA, Weitz J, Rahbari N, Reissfelder C, Pilarsky C, Fraga MF, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 2015;523:177–82.
    1. An M, Lohse I, Tan Z, Zhu J, Wu J, Kurapati H, Morgan MA, Lawrence TS, Cuneo KC, Lubman DM. Quantitative proteomic analysis of serum exosomes from patients with locally advanced pancreatic cancer undergoing chemoradiotherapy. J Proteome Res. 2017;16:1763–72.
    1. Ning K, Wang T, Sun X, Zhang P, Chen Y, Jin J, Hua D. UCH-L1-containing exosomes mediate chemotherapeutic resistance transfer in breast cancer. J Surg Oncol. 2017;115:932–40.
    1. Pan L, Liang W, Fu M, Huang ZH, Li X, Zhang W, Zhang P, Qian H, Jiang PC, Xu WR, Zhang X. Exosomes-mediated transfer of long noncoding RNA ZFAS1 promotes gastric cancer progression. J Cancer Res Clin Oncol. 2017;143:991–1004.
    1. Tsukamoto M, Iinuma H, Yagi T, Matsuda K, Hashiguchi Y. Circulating exosomal microRNA-21 as a biomarker in each tumor stage of colorectal cancer. Oncology. 2017;92:360–70.
    1. Hu Y, Li D, Wu A, Qiu X, Di W Huang L, Qiu L. TWEAK-stimulated macrophages inhibit metastasis of epithelial ovarian cancer via exosomal shuttling of microRNA. Cancer Lett. 2017;393:60–7.
    1. Frontela Noda M. [MicroRNAs in cancer: from research to clinical practice]. [Article in Spanish] Rev Cubana Med. 2012;51:325–35.
    1. Etheridge A, Lee I, Hood L, Galas D, Wang K. Extracellular microRNA: A new source of biomarkers. Mutat Res. 2011;717:85–90.
    1. Resnick KE, Alder H, Hagan JP, Richardson DL, Croce CM, Cohn DE. The detection of differentially expressed microRNAs from the serum of ovarian cancer patients using a novel real-time PCR platform. Gynecol Oncol. 2009;112:55–9.
    1. Xie P, Li X, Tan X, Sun X, Wang C, Yu J. Sequential serum let-7 is a novel biomarker to predict accelerated reproliferation during fractional radiotherapy in lung cancer. Clin Lung Cancer. 2016;17:e95–e101.
    1. Shen LQ, Xie YZ, Qian XF, Zhuang ZX, Jiao Y, Qi XF. A single nucleotide polymorphism in the promoter region of let-7 family is associated with lung cancer risk in Chinese. Genet Mol Res. 2015;14:4505–12.
    1. Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005;102:13944–9.
    1. Welch C, Chen Y, Stallings RL. MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells. Oncogene. 2007;26:5017–22.
    1. Tazawa H, Tsuchiya N, Izumiya M, Nakagama H. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci U S A. 2007;104:15472–7.
    1. Mendell JT. miRiad roles for the miR-17-92 cluster in development and disease. Cell. 2008;133:217–22.
    1. Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, Yatabe Y, Kawahara K, Sekido Y, Takahashi T. A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 2005;65:9628–32.
    1. He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, Hammond SM. A microRNA polycistron as a potential human oncogene. Nature. 2005;435:828–33.
    1. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007;133:647–58.
    1. Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH. Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem. 2008;283:1026–33.
    1. Zhu FQ, Zeng L, Tang N, Tang YP, Zhou BP, Li FF, Wu WG, Zeng XB, Peng SS. MicroRNA-155 downregulation promotes cell cycle arrest and apoptosis in diffuse large B-cell lymphoma. Oncol Res. 2016;24:415–27.
    1. Zhang XF, Tu R, Li K, Ye P, Cui X. Tumor suppressor PTPRJ is a target of miR-155 in colorectal cancer. J Cell Biochem. 2017;118:3391–400.
    1. Voorhoeve PM, le Sage C, Schrier M, Gillis AJ, Stoop H, Nagel R, Liu YP, van Duijse J, Drost J, Griekspoor A, Zlotorynski E, Yabuta N, De Vita G, et al. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell. 2006;124:1169–81.
    1. Kan CW, Hahn MA, Gard GB, Maidens J, Huh JY, Marsh DJ, Howell VM. Elevated levels of circulating microRNA-200 family members correlate with serous epithelial ovarian cancer. BMC Cancer. 2012;12:627.
    1. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O'Briant KC, Allen A, Lin DW, Urban N, Drescher CW, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008;105:10513–8.
    1. Boreal Genomics OnTarget Mutation Detection Panels. 2017.
    1. Trovagene Diagnostics Trovera. 2017.
    1. RainDance Technologies ThunderBolts Cancer Panel. 2017.
    1. RainDance Technologies ThunderBolts Myeloid Panel. 2017.
    1. Inviata Invision. 2017.
    1. Pathway Genomics Cancer Monitoring Liquid Biopsy Blood Testing. 2017.
    1. El Messaoudi S, Rolet F, Mouliere F, Thierry AR. Circulating cell free DNA: Preanalytical considerations. Clin Chim Acta. 2013;424:222–30.
    1. Spindler KL. Methodological, biological and clinical aspects of circulating free DNA in metastatic colorectal cancer. Acta Oncol (Madr) 2017;56:7–16.
    1. Haber D, Velculescu V. Blood-based analysis of cancer: Circulating tumor cells and circulating tumor DNA. Cancer Discov. 2014;4:650–61.
    1. He Q, Johnston J, Zeitlinger J, City K, City K. Liquid biopsies: Genotyping circulating tumor DNA. J Clin Oncol. 2015;33:395–401.
    1. Wang W, Song Z, Zhang Y. A comparison of ddPCR and ARMS for detecting EGFR T790M status in ctDNA from advanced NSCLC patients with acquired EGFR-TKI resistance. Cancer Med. 2017;6:154–62.
    1. Imamura F, Uchida J, Kukita Y, Kumagai T, Nishino K, Inoue T, Kimura M, Oba S, Kato K. Monitoring of treatment responses and clonal evolution of tumor cells by circulating tumor DNA of heterogeneous mutant EGFR genes in lung cancer. Lung Cancer. 2016;94:68–73.
    1. Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, Le Quesne J, Moore DA, Veeriah S, Rosenthal R, Marafioti T, Kirkizlar E, Watkins TB, et al. Phylogenetic ctDNA analysis depicts early stage lung cancer evolution. Nature. 2017;545:446–51.
    1. Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS, Sougnez C, Stewart C, Sivachenko A, Wang L, Wan Y, Zhang W, Shukla SA, et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell. 2013;152:714–26.
    1. Imamura T, Komatsu S, Ichikawa D, Kawaguchi T, Miyamae M, Okajima W, Ohashi T, Arita T, Konishi H, Shiozaki A, Morimura R, Ikoma H, Okamoto K, et al. Liquid biopsy in patients with pancreatic cancer: Circulating tumor cells and cell-free nucleic acids. World J Gastroenterol. 2016;22:5627–41.

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