Zusammenfassung
Der Nachweis genetischer Veränderungen in Körperflüssigkeiten als Ergänzung oder gar Ersatz der konventionellen gewebebasierten Tumordiagnostik ist ein aktuell in Forschung und Industrie viel beachtetes und diskutiertes Thema. Technische Fortschritte in der Nukleinsäureanalytik im Verbund mit vielversprechenden Studienergebnissen haben sehr große Erwartungen geweckt bezüglich Früherkennung, Diagnostik, Prognostik und Monitoring von Tumorerkrankungen mithilfe einer minimalinvasiven Blutprobe. Einzelne fokussierte Assays haben bereits Eingang in die Routinediagnostik gefunden und stellen eine sinnvolle Ergänzung zur etablierten Tumordiagnostik dar, wenn eine Gewebeprobe nicht gewonnen werden kann. Vor einer Ausweitung des Einsatzes von Liquid Biopsy außerhalb von Studien und des Nachweises komplexer Marker im peripheren Blut (wie z. B. der Tumormutationslast) sind aber zahlreiche methodische Herausforderungen und konzeptionelle Probleme zu lösen. Der vorliegende Artikel konzentriert sich auf den Nachweis freier zirkulierender Tumor-DNA im Blutplasma und diskutiert kritisch Anwendungsfelder und Potenziale sowie Herausforderungen und Grenzen dieser Methodik.
Abstract
The detection of tumor-specific genetic alterations in body fluids as an addition to or even replacement for established tissue-based tumor diagnostics is currently a hot topic in academic research and industry. Progress in methods for nucleic acid analyses together with promising results from clinical studies have raised great expectations for cancer screening, diagnosis, prognosis, and therapy monitoring by means of a minimally invasive blood draw. Individual focused assays have already been introduced into routine diagnostics and represent a valuable option in cases where no tissue samples are available. However, before the use of liquid biopsy outside of clinical studies is enforced and more complex markers (like tumor mutational burden) are analyzed, several practical challenges and principal problems have to be addressed. This review focusses on the detection of free-circulating nucleic acids in blood plasma and critically discusses established and future applications as well as challenges and limitations of this new method.
Literatur
Bartels S, Christgen M, Luft A et al (2018) Estrogen receptor (ESR1) mutation in bone metastases from breast cancer. Mod Pathol 31:56–61
Bartels S, Persing S, Hasemeier B et al (2017) Molecular analysis of circulating cell-free DNA from lung cancer patients in routine laboratory practice: a cross-platform comparison of three different molecular methods for mutation detection. J Mol Diagn 19:722–732
Brown HK, Tellez-Gabriel M, Cartron PF et al (2018) Characterization of circulating tumor cells as a reflection of the tumor heterogeneity: myth or reality? Drug Discov Today 24:763–772
Busque L, Patel JP, Figueroa ME et al (2012) Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 44:1179–1181
Cabel L, Proudhon C, Gortais H et al (2017) Circulating tumor cells: clinical validity and utility. Int J Clin Oncol 22:421–430
Conrads TP, Zhou M, Petricoin EF 3rd et al (2003) Cancer diagnosis using proteomic patterns. Expert Rev Mol Diagn 3:411–420
Corcoran RB, Chabner BA (2018) Application of cell-free DNA analysis to cancer treatment. N Engl J Med 379:1754–1765
Crowley E, Di Nicolantonio F, Loupakis F et al (2013) Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol 10:472–484
De Rubis G, Rajeev Krishnan S, Bebawy M (2019) Liquid biopsies in cancer diagnosis, monitoring, and prognosis. Trends Pharmacol Sci 136:35–44
Diamandis EP (2004) Mass spectrometry as a diagnostic and a cancer biomarker discovery tool: opportunities and potential limitations. Mol Cell Proteomics 3:367–378
Fassunke J, Ihle MA, Lenze D et al (2017) EGFR T790M mutation testing of non-small cell lung cancer tissue and blood samples artificially spiked with circulating cell-free tumor DNA: results of a round robin trial. Virchows Arch 471:509–520
Fiala C, Diamandis EP (2018) Utility of circulating tumor DNA in cancer diagnostics with emphasis on early detection. BMC Med 16:166
Griewank KG, Wiesner T, Murali R et al (2018) Atypical fibroxanthoma and pleomorphic dermal sarcoma harbor frequent NOTCH1/2 and FAT1 mutations and similar DNA copy number alteration profiles. Mod Pathol 31:418–428
Heitzer E, Haque IS, Roberts CES et al (2019) Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat Rev Genet 20:71–88
Heuser M, Thol F, Ganser A (2016) Clonal Hematopoiesis of Indeterminate Potential. Dtsch Arztebl Int 113:317–322
Hsiao YC, Chu LJ, Chen JT et al (2017) Proteomic profiling of the cancer cell secretome: informing clinical research. Expert Rev Proteomics 14:737–756
Jaiswal S, Fontanillas P, Flannick J et al (2014) Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371:2488–2498
Jaiswal S, Natarajan P, Silver AJ et al (2017) Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 377:111–121
Ko J, Baldassano SN, Loh PL et al (2018) Machine learning to detect signatures of disease in liquid biopsies—a user’s guide. Lab Chip 18:395–405
Leung F, Kulasingam V, Diamandis EP et al (2016) Circulating tumor DNA as a cancer biomarker: fact or fiction? Clin Chem 62:1054–1060
Li BT, Stephens D, Chaft JE et al (2017) Liquid biopsy for ctDNA to revolutionize the care of patients with early stage lung cancers. Ann Transl Med 5:479
Liu J, Chen X, Wang J et al (2018) Biological background of the genomic variations of cf-DNA in healthy individuals. Ann Oncol 30:464–470
Lucchetti D, Fattorossi A, Sgambato A (2019) Extracellular vesicles in oncology: progress and pitfalls in the methods of isolation and analysis. Biotechnol J 14:e1700716
Nilsson RJ, Karachaliou N, Berenguer J et al (2016) Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer. Oncotarget 7:1066–1075
Ricciuti B, Baglivo S, Paglialunga L et al (2017) Osimertinib in patients with advanced epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer: rationale, evidence and place in therapy. Ther Adv Med Oncol 9:387–404
Sole C, Arnaiz E, Manterola L et al (2019) The circulating transcriptome as a source of cancer liquid biopsy biomarkers. Semin Cancer Biol. https://doi.org/10.1016/j.semcancer.2019.01.003
Stewart CM, Kothari PD, Mouliere F et al (2018) The value of cell-free DNA for molecular pathology. J Pathol 244:616–627
Tong Y, Shen S, Jiang H et al (2017) Application of digital PCR in detecting human diseases associated gene mutation. Cell Physiol Biochem 43:1718–1730
Torga G, Pienta KJ (2018) Patient-paired sample congruence between 2 commercial liquid biopsy tests. JAMA Oncol 4:868–870
Torga G, Pienta KJ (2018) Regarding the congruence between 2 circulating tumor DNA sequencing assays-reply. JAMA Oncol 4:1431–1432
Wan JCM, Massie C, Garcia-Corbacho J et al (2017) Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer 17:223–238
Zheng MM, Li YS, Jiang BY et al (2019) Brief report: clinical utility of cerebrospinal fluid cell free-DNA as liquid biopsy for leptomeningeal metastases in ALK-rearranged NSCLC. J Thorac Oncol. https://doi.org/10.1016/j.jtho.2019.01.007
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Interessenkonflikt
U. Lehmann und S. Bartels geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.
Additional information
Dieser Beitrag wurde in der Zeitschrift Der Pathologe 3/2019 · 40:250–255, https://doi.org/10.1007/s00292-019-0604-5 erstveröffentlicht. Zweitpublikation mit freundlicher Genehmigung der Autoren.
Rights and permissions
About this article
Cite this article
Lehmann, U., Bartels, S. Liquid Biopsy in der Tumordiagnostik. Wien klin Mag 23, 38–43 (2020). https://doi.org/10.1007/s00740-019-00314-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00740-019-00314-3