Skip to main content

Tipp

Weitere Artikel dieser Ausgabe durch Wischen aufrufen

Erschienen in: Wiener klinisches Magazin 2/2016

01.04.2016 | Genetik

Ein vielversprechendes Werkzeug

Therapiesteuerung anhand zellfreier, zirkulierender Tumor-DNA

verfasst von: Ass.-Prof. Priv.-Doz. Mag. Dr. Ellen Heitzer

Erschienen in: Wiener klinisches Magazin | Ausgabe 2/2016

Einloggen, um Zugang zu erhalten
share
TEILEN

Zusammenfassung

Durch die zunehmende Anzahl an zielgerichteten Therapien kommt es in der Behandlung von Krebserkrankungen zu einem Paradigmenwechsel. Die molekulargenetische Diagnostik und kontinuierliche Charakterisierung der Tumore gewinnt daher zunehmend an Bedeutung. In den meisten Fällen sind aber wiederholte Gewebsentnahmen eines Tumors und dessen Metastasen nicht durchführbar, weshalb eine Analyse von tumorspezifischen Veränderungen aus Blut bzw. Plasma oder Serum vorteilhaft wäre. Wiederholte Blutabnahmen sind einfach, schnell und kostengünstig zu bewerkstelligen, ohne den Patienten zu belasten. Zellfreie, zirkulierende DNA-Fragmente (ctDNA), welche von unterschiedlichen Tumorlokalisationen in die Zirkulation entlassen werden, reflektieren die Veränderungen im Tumorgenom in Echtzeit und erlauben somit eine Überwachung während des gesamten Therapieverlaufs und darüber hinaus. Unzählige Studien haben die klinische Relevanz von ctDNA als diagnostischen, prädiktiven und prognostischen Biomarker belegt. In dieser Übersichtsarbeit werden die Biologie, methodische Ansätze sowie das Potenzial der ctDNA zu Überwachung des Therapieansprechens diskutiert.
Literatur
1.
Zurück zum Zitat Alizadeh AA, Aranda V, Bardelli A, Blanpain C, Bock C, Borowski C et al (2015) Toward understanding and exploiting tumor heterogeneity. Nat Med 21:846–853 CrossRefPubMed Alizadeh AA, Aranda V, Bardelli A, Blanpain C, Bock C, Borowski C et al (2015) Toward understanding and exploiting tumor heterogeneity. Nat Med 21:846–853 CrossRefPubMed
2.
Zurück zum Zitat Gerlinger M (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366:883–892 CrossRefPubMed Gerlinger M (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366:883–892 CrossRefPubMed
3.
4.
Zurück zum Zitat McGranahan N, Swanton C (2015) Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell 27:15–26 CrossRefPubMed McGranahan N, Swanton C (2015) Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell 27:15–26 CrossRefPubMed
5.
6.
Zurück zum Zitat Mandel P, Metais P (1948) Les acides nucleiques du plasma sanguin chez l’homme. C R Seances Soc Biol Fil 142:241–243 PubMed Mandel P, Metais P (1948) Les acides nucleiques du plasma sanguin chez l’homme. C R Seances Soc Biol Fil 142:241–243 PubMed
7.
Zurück zum Zitat Leon SA, Ehrlich GE, Shapiro B, Labbate VA (1977) Free DNA in the serum of rheumatoid arthritis patients. J Rheumatol 4:139–143 PubMed Leon SA, Ehrlich GE, Shapiro B, Labbate VA (1977) Free DNA in the serum of rheumatoid arthritis patients. J Rheumatol 4:139–143 PubMed
8.
Zurück zum Zitat Stroun M, Anker P, Maurice P, Lyautey J, Lederrey C, Beljanski M (1989) Neoplastic characteristics of the DNA found in the plasma of cancer patients. Oncology 46:318–322 CrossRefPubMed Stroun M, Anker P, Maurice P, Lyautey J, Lederrey C, Beljanski M (1989) Neoplastic characteristics of the DNA found in the plasma of cancer patients. Oncology 46:318–322 CrossRefPubMed
9.
Zurück zum Zitat Heitzer E, Ulz P, Geigl JB (2015) Circulating tumor DNA as a liquid biopsy for cancer. Clin Chem 61:112–123 CrossRefPubMed Heitzer E, Ulz P, Geigl JB (2015) Circulating tumor DNA as a liquid biopsy for cancer. Clin Chem 61:112–123 CrossRefPubMed
10.
Zurück zum Zitat Stroun M, Lyautey J, Lederrey C, Olson-Sand A, Anker P (2001) About the possible origin and mechanism of circulating DNA apoptosis and active DNA release. Clin Chim Acta 313:139–142 CrossRefPubMed Stroun M, Lyautey J, Lederrey C, Olson-Sand A, Anker P (2001) About the possible origin and mechanism of circulating DNA apoptosis and active DNA release. Clin Chim Acta 313:139–142 CrossRefPubMed
11.
Zurück zum Zitat Jahr S (2001) DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res 61:1659–1665 PubMed Jahr S (2001) DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res 61:1659–1665 PubMed
12.
Zurück zum Zitat Diehl F, Li M, Dressman D, He Y, Shen D, Szabo S et al (2005) Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci USA 102:16368–16373 CrossRefPubMedPubMedCentral Diehl F, Li M, Dressman D, He Y, Shen D, Szabo S et al (2005) Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci USA 102:16368–16373 CrossRefPubMedPubMedCentral
13.
Zurück zum Zitat Sikora K, Bedin C, Vicentini C, Malpeli G, D’Angelo E, Sperandio N et al (2015) Evaluation of cell-free DNA as a biomarker for pancreatic malignancies. Int J Biol Markers 30:e136–e141 CrossRefPubMed Sikora K, Bedin C, Vicentini C, Malpeli G, D’Angelo E, Sperandio N et al (2015) Evaluation of cell-free DNA as a biomarker for pancreatic malignancies. Int J Biol Markers 30:e136–e141 CrossRefPubMed
14.
16.
Zurück zum Zitat Heitzer E, Auer M, Hoffmann EM, Pichler M, Gasch C, Ulz P et al (2013) Establishment of tumor-specific copy number alterations from plasma DNA of patients with cancer. Int J Cancer J Int Du Cancer 133:346–356 CrossRef Heitzer E, Auer M, Hoffmann EM, Pichler M, Gasch C, Ulz P et al (2013) Establishment of tumor-specific copy number alterations from plasma DNA of patients with cancer. Int J Cancer J Int Du Cancer 133:346–356 CrossRef
17.
Zurück zum Zitat Garcia-Olmo DC, Garcia-Olmo D (2013) Biological role of cell-free nucleic acids in cancer: the theory of genometastasis. Crit Rev Oncog 18:153–161 CrossRefPubMed Garcia-Olmo DC, Garcia-Olmo D (2013) Biological role of cell-free nucleic acids in cancer: the theory of genometastasis. Crit Rev Oncog 18:153–161 CrossRefPubMed
18.
Zurück zum Zitat Garcia-Olmo D, Garcia-Olmo DC, Dominguez-Berzosa C, Guadalajara H, Vega L, Garcia-Arranz M (2012) Oncogenic transformation induced by cell-free nucleic acids circulating in plasma (genometastasis) remains after the surgical resection of the primary tumor: A pilot study. Expert Opin Biol Ther 12(Suppl 1):S61–S68 CrossRefPubMed Garcia-Olmo D, Garcia-Olmo DC, Dominguez-Berzosa C, Guadalajara H, Vega L, Garcia-Arranz M (2012) Oncogenic transformation induced by cell-free nucleic acids circulating in plasma (genometastasis) remains after the surgical resection of the primary tumor: A pilot study. Expert Opin Biol Ther 12(Suppl 1):S61–S68 CrossRefPubMed
19.
Zurück zum Zitat Snyder MW, Kircher M, Hill AJ, Daza RM, Shendure J (2016) Cell-free DNA comprises an in vivo nucleosome footprint that informs its tissues-of-origin. Cell 164:57–68 CrossRefPubMed Snyder MW, Kircher M, Hill AJ, Daza RM, Shendure J (2016) Cell-free DNA comprises an in vivo nucleosome footprint that informs its tissues-of-origin. Cell 164:57–68 CrossRefPubMed
20.
Zurück zum Zitat Sun K, Jiang P, Chan KC, Wong J, Cheng YK, Liang RH et al (2015) Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments. Proc Natl Acad Sci USA 112:E5503–E5512 CrossRefPubMedPubMedCentral Sun K, Jiang P, Chan KC, Wong J, Cheng YK, Liang RH et al (2015) Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments. Proc Natl Acad Sci USA 112:E5503–E5512 CrossRefPubMedPubMedCentral
21.
Zurück zum Zitat Lo YM, Chan KC, Sun H, Chen EZ, Jiang P, Lun FM et al (2010) Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Sci Transl Med 2:61ra91 PubMed Lo YM, Chan KC, Sun H, Chen EZ, Jiang P, Lun FM et al (2010) Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Sci Transl Med 2:61ra91 PubMed
22.
24.
Zurück zum Zitat Spindler KL, Pallisgaard N, Vogelius I, Jakobsen A (2012) Quantitative cell-free DNA, kras, and braf mutations in plasma from patients with metastatic colorectal cancer during treatment with cetuximab and irinotecan. Clin Cancer Res 18:1177–1185 CrossRefPubMed Spindler KL, Pallisgaard N, Vogelius I, Jakobsen A (2012) Quantitative cell-free DNA, kras, and braf mutations in plasma from patients with metastatic colorectal cancer during treatment with cetuximab and irinotecan. Clin Cancer Res 18:1177–1185 CrossRefPubMed
25.
Zurück zum Zitat Taly V, Pekin D, Benhaim L, Kotsopoulos SK, Le Corre D, Li X et al (2013) Multiplex picodroplet digital pcr to detect kras mutations in circulating DNA from the plasma of colorectal cancer patients. Clin Chem 59:1722–1731 CrossRefPubMed Taly V, Pekin D, Benhaim L, Kotsopoulos SK, Le Corre D, Li X et al (2013) Multiplex picodroplet digital pcr to detect kras mutations in circulating DNA from the plasma of colorectal cancer patients. Clin Chem 59:1722–1731 CrossRefPubMed
26.
27.
Zurück zum Zitat Forshew T, Murtaza M, Parkinson C, Gale D, Tsui DW, Kaper F et al (2012) Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med 4:136ra68 PubMed Forshew T, Murtaza M, Parkinson C, Gale D, Tsui DW, Kaper F et al (2012) Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med 4:136ra68 PubMed
28.
Zurück zum Zitat Newman AM, Bratman SV, To J, Wynne JF, Eclov NC, Modlin LA et al (2014) An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med 20(5):548–554 CrossRefPubMedPubMedCentral Newman AM, Bratman SV, To J, Wynne JF, Eclov NC, Modlin LA et al (2014) An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med 20(5):548–554 CrossRefPubMedPubMedCentral
29.
Zurück zum Zitat Leary RJ, Sausen M, Kinde I, Papadopoulos N, Carpten JD, Craig D et al (2012) Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. Sci Transl Med 4:162ra54 Leary RJ, Sausen M, Kinde I, Papadopoulos N, Carpten JD, Craig D et al (2012) Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. Sci Transl Med 4:162ra54
30.
Zurück zum Zitat Chan KC (2013) Cancer genome scanning in plasma: Detection of tumor-associated copy number aberrations, single-nucleotide variants, and tumoral heterogeneity by massively parallel sequencing. Clin Chem 59:211–224 CrossRefPubMed Chan KC (2013) Cancer genome scanning in plasma: Detection of tumor-associated copy number aberrations, single-nucleotide variants, and tumoral heterogeneity by massively parallel sequencing. Clin Chem 59:211–224 CrossRefPubMed
31.
Zurück zum Zitat Heitzer E, Auer M, Gasch C, Pichler M, Ulz P, Hoffmann EM et al (2013) Complex tumor genomes inferred from single circulating tumor cells by array-cgh and next-generation sequencing. Cancer Res 73:2965–2975 CrossRefPubMed Heitzer E, Auer M, Gasch C, Pichler M, Ulz P, Hoffmann EM et al (2013) Complex tumor genomes inferred from single circulating tumor cells by array-cgh and next-generation sequencing. Cancer Res 73:2965–2975 CrossRefPubMed
32.
Zurück zum Zitat Heitzer E, Ulz P, Belic J, Gutschi S, Quehenberger F, Fischereder K et al (2013) Tumor-associated copy number changes in the circulation of patients with prostate cancer identified through whole-genome sequencing. Genome Med 5:30 CrossRefPubMedPubMedCentral Heitzer E, Ulz P, Belic J, Gutschi S, Quehenberger F, Fischereder K et al (2013) Tumor-associated copy number changes in the circulation of patients with prostate cancer identified through whole-genome sequencing. Genome Med 5:30 CrossRefPubMedPubMedCentral
33.
Zurück zum Zitat Belic J, Koch M, Ulz P, Auer M, Gerhalter T, Mohan S et al (2015) Rapid identification of plasma DNA samples with increased ctdna levels by a modified fast-seqs approach. Clin Chem 61:838–849 CrossRefPubMed Belic J, Koch M, Ulz P, Auer M, Gerhalter T, Mohan S et al (2015) Rapid identification of plasma DNA samples with increased ctdna levels by a modified fast-seqs approach. Clin Chem 61:838–849 CrossRefPubMed
34.
Zurück zum Zitat Sozzi G, Conte D, Leon M, Ciricione R, Roz L, Ratcliffe C et al (2003) Quantification of free circulating DNA as a diagnostic marker in lung cancer. J Clin Oncol 21:3902–3908 CrossRefPubMed Sozzi G, Conte D, Leon M, Ciricione R, Roz L, Ratcliffe C et al (2003) Quantification of free circulating DNA as a diagnostic marker in lung cancer. J Clin Oncol 21:3902–3908 CrossRefPubMed
35.
Zurück zum Zitat Sozzi G, Conte D, Mariani L, Lo Vullo S, Roz L, Lombardo C et al (2001) Analysis of circulating tumor DNA in plasma at diagnosis and during follow-up of lung cancer patients. Cancer Res 61:4675–4678 PubMed Sozzi G, Conte D, Mariani L, Lo Vullo S, Roz L, Lombardo C et al (2001) Analysis of circulating tumor DNA in plasma at diagnosis and during follow-up of lung cancer patients. Cancer Res 61:4675–4678 PubMed
36.
Zurück zum Zitat Chen X, Bonnefoi H, Diebold-Berger S, Lyautey J, Lederrey C, Faltin-Traub E et al (1999) Detecting tumor-related alterations in plasma or serum DNA of patients diagnosed with breast cancer. Clin Cancer Res 5:2297–2303 PubMed Chen X, Bonnefoi H, Diebold-Berger S, Lyautey J, Lederrey C, Faltin-Traub E et al (1999) Detecting tumor-related alterations in plasma or serum DNA of patients diagnosed with breast cancer. Clin Cancer Res 5:2297–2303 PubMed
37.
Zurück zum Zitat Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N et al (2014) Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6:224ra24 CrossRefPubMedPubMedCentral Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N et al (2014) Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6:224ra24 CrossRefPubMedPubMedCentral
38.
Zurück zum Zitat Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF et al (2013) Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 368:1199–1209 CrossRefPubMed Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF et al (2013) Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 368:1199–1209 CrossRefPubMed
39.
Zurück zum Zitat Olsson E, Winter C, George A, Chen Y, Howlin J, Tang MH et al (2015) Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO Mol Med 7:1034–1047 CrossRefPubMedPubMedCentral Olsson E, Winter C, George A, Chen Y, Howlin J, Tang MH et al (2015) Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO Mol Med 7:1034–1047 CrossRefPubMedPubMedCentral
40.
Zurück zum Zitat Sorensen BS, Wu L, Wei W, Tsai J, Weber B, Nexo E, Meldgaard P (2014) Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and resistance mutations in the plasma DNA of patients with advanced non-small cell lung cancer during treatment with erlotinib. Cancer 120:3896–3901 CrossRefPubMedPubMedCentral Sorensen BS, Wu L, Wei W, Tsai J, Weber B, Nexo E, Meldgaard P (2014) Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and resistance mutations in the plasma DNA of patients with advanced non-small cell lung cancer during treatment with erlotinib. Cancer 120:3896–3901 CrossRefPubMedPubMedCentral
41.
Zurück zum Zitat Jiang T, Ren S, Zhou C (2015) Role of circulating-tumor DNA analysis in non-small cell lung cancer. Lung Cancer 90:128–134 CrossRefPubMed Jiang T, Ren S, Zhou C (2015) Role of circulating-tumor DNA analysis in non-small cell lung cancer. Lung Cancer 90:128–134 CrossRefPubMed
42.
Zurück zum Zitat Oxnard GR, Paweletz CP, Kuang Y, Mach SL, O’Connell A, Messineo MM et al (2014) Noninvasive detection of response and resistance in egfr-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clin Cancer Res 20:1698–1705 CrossRefPubMedPubMedCentral Oxnard GR, Paweletz CP, Kuang Y, Mach SL, O’Connell A, Messineo MM et al (2014) Noninvasive detection of response and resistance in egfr-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clin Cancer Res 20:1698–1705 CrossRefPubMedPubMedCentral
43.
Zurück zum Zitat Qiu M, Wang J, Xu Y, Ding X, Li M, Jiang F et al (2015) Circulating tumor DNA is effective for the detection of egfr mutation in non-small cell lung cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev A Publ Am Assoc Cancer Res 24:206–212 (cosponsored by the American Society of Preventive Oncology) CrossRef Qiu M, Wang J, Xu Y, Ding X, Li M, Jiang F et al (2015) Circulating tumor DNA is effective for the detection of egfr mutation in non-small cell lung cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev A Publ Am Assoc Cancer Res 24:206–212 (cosponsored by the American Society of Preventive Oncology) CrossRef
44.
Zurück zum Zitat Diaz LA Jr (2012) The molecular evolution of acquired resistance to targeted egfr blockade in colorectal cancers. Nature 486:537–540 PubMedPubMedCentral Diaz LA Jr (2012) The molecular evolution of acquired resistance to targeted egfr blockade in colorectal cancers. Nature 486:537–540 PubMedPubMedCentral
45.
Zurück zum Zitat Mohan S, Heitzer E, Ulz P, Lafer I, Lax S, Auer M et al (2014) Changes in colorectal carcinoma genomes under anti-egfr therapy identified by whole-genome plasma DNA sequencing. PLoS Genet 10:e1004271 CrossRefPubMedPubMedCentral Mohan S, Heitzer E, Ulz P, Lafer I, Lax S, Auer M et al (2014) Changes in colorectal carcinoma genomes under anti-egfr therapy identified by whole-genome plasma DNA sequencing. PLoS Genet 10:e1004271 CrossRefPubMedPubMedCentral
46.
Zurück zum Zitat Heitzer E, Ulz P, Geigl JB, Speicher MR (2015) Non-invasive detection of genome-wide somatic copy number alterations by liquid biopsies. Mol Oncol. doi:10.1007/s00740-016-0099-0 PubMed Heitzer E, Ulz P, Geigl JB, Speicher MR (2015) Non-invasive detection of genome-wide somatic copy number alterations by liquid biopsies. Mol Oncol. doi:10.1007/s00740-016-0099-0 PubMed
47.
Zurück zum Zitat Tie J, Kinde I, Wang Y, Wong HL, Roebert J, Christie M et al (2015) Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol 26:1715–1722 CrossRefPubMed Tie J, Kinde I, Wang Y, Wong HL, Roebert J, Christie M et al (2015) Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol 26:1715–1722 CrossRefPubMed
48.
Zurück zum Zitat Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM et al (2013) Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497:108–112 CrossRefPubMed Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM et al (2013) Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497:108–112 CrossRefPubMed
49.
Zurück zum Zitat Heidary M, Auer M, Ulz P, Heitzer E, Petru E, Gasch C et al (2014) The dynamic range of circulating tumor DNA in metastatic breast cancer. Breast Cancer Res 16:421 CrossRefPubMedPubMedCentral Heidary M, Auer M, Ulz P, Heitzer E, Petru E, Gasch C et al (2014) The dynamic range of circulating tumor DNA in metastatic breast cancer. Breast Cancer Res 16:421 CrossRefPubMedPubMedCentral
Metadaten
Titel
Ein vielversprechendes Werkzeug
Therapiesteuerung anhand zellfreier, zirkulierender Tumor-DNA
verfasst von
Ass.-Prof. Priv.-Doz. Mag. Dr. Ellen Heitzer
Publikationsdatum
01.04.2016
Verlag
Springer Vienna
Erschienen in
Wiener klinisches Magazin / Ausgabe 2/2016
Print ISSN: 1869-1757
Elektronische ISSN: 1613-7817
DOI
https://doi.org/10.1007/s00740-016-0099-0

Weitere Artikel der Ausgabe 2/2016

Wiener klinisches Magazin 2/2016 Zur Ausgabe

Panorama

Panorama