Advertisement

Tumor Biology

, Volume 35, Issue 2, pp 1183–1191 | Cite as

Diagnostic relevance of plasma DNA and DNA integrity for breast cancer

  • Oliver J. Stötzer
  • Julia Lehner
  • Debora Fersching-Gierlich
  • Dorothea Nagel
  • Stefan Holdenrieder
Research Article

Abstract

Levels of ALU 115, ALU 247, DNA integrity ([1, 2]) and of the tumour markers CA 15–3 and CEA were analysed in the blood of 152 patients. Plasma levels of ALU 115 and ALU 247 were significantly higher in patients with locally confined (LBC; N = 65), metastatic breast cancer (MBC; N = 47), and benign diseases (N = 12) than in healthy controls (p < 0.001 for all comparisons). DNA integrity, CEA, and CA 15–3 were significantly higher in MBC than in benign controls and LBC but could not identify LBCs. The best discrimination of LBC from healthy controls was achieved by ALU 115 and ALU 247 (AUC 95.4 and 95.5 %) and of MBC from all control groups by CA 15–3 and CEA (AUC 83.2 and 79.1 %). Plasma DNA is valuable for the detection of LBC, while established tumour markers are most informative in MBC.

Keywords

Plasma DNA DNA integrity Breast cancer Neoadjuvant chemotherapy 

Notes

Acknowledgments

This work is part of the doctoral thesis of Julia Lehner.

Conflicts of interest

None

Supplementary material

13277_2013_1158_MOESM1_ESM.doc (85 kb)
ESM 1 (DOC 85 kb)
13277_2013_1158_MOESM2_ESM.doc (470 kb)
ESM 2 (DOC 469 kb)
13277_2013_1158_MOESM3_ESM.pdf (234 kb)
ESM 3 (PDF 234 kb)

References

  1. 1.
    Umetani N, Giuliano AE, Hiramatsu SH, Amersi F, Nakagawa T, Martino S, et al. Prediction of breast tumor progression by integrity of free circulating DNA in serum. J Clin Oncol. 2006;24(26):4270–6.Google Scholar
  2. 2.
    Umetani N, Kim J, Hiramatsu S, Reber HA, Hines OJ, Bilchik AJ, et al. Increased integrity of free circulating DNA in sera of patients with colorectal or periampullary cancer: direct quantitative PCR for ALU repeats. Clin Chem. 2006;52(6):1062–9.Google Scholar
  3. 3.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.Google Scholar
  4. 4.
    Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005;353(17):1784–92.Google Scholar
  5. 5.
    Laessig D, Nagel D, Heinemann V, Untch M, Kahlert S, Bauerfeind I, et al. Importance of CEA and CA 15–3 during disease progression in metastatic breast cancer patients. Anticancer Res. 2007;27(4A):1963–8.Google Scholar
  6. 6.
    Stieber P LD, Heinemann V, Untch M, Kahlert S, Nagel D. Kinetics of CEA and CA 15–3 correlate with response in patients undergoing chemotherapy for metastatic breast cancer. J Clin Oncol, ASCO Annual Meeting Proceedings. 2007;25((S18):):1087.Google Scholar
  7. 7.
    Sturgeon CM, Duffy MJ, Stenman UH, Lilja H, Brunner N, Chan DW, et al. National academy of clinical biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem. 2008;54(12):e11–79.Google Scholar
  8. 8.
    Chiu TW, Young R, Chan LY, Burd A, Lo DY. Plasma cell-free DNA as an indicator of severity of injury in burn patients. Clin Chem Lab Med. 2006;44(1):13–7.Google Scholar
  9. 9.
    Zeerleder S, Zwart B, Wuillemin WA, Aarden LA, Groeneveld AB, Caliezi C, et al. Elevated nucleosome levels in systemic inflammation and sepsis. Crit Care Med. 2003;31(7):1947–51.Google Scholar
  10. 10.
    Lam NY, Rainer TH, Wong LK, Lam W, Lo YM. Plasma DNA as a prognostic marker for stroke patients with negative neuroimaging within the first 24 h of symptom onset. Resuscitation. 2006;68(1):71–8.Google Scholar
  11. 11.
    Holdenrieder S, Eichhorn P, Beuers U, Samtleben W, Schoenermarck U, Zachoval R, et al. Nucleosomal DNA fragments in autoimmune diseases. Ann N Y Acad Sci. 2006;1075:318–27.Google Scholar
  12. 12.
    Holdenrieder S, Stieber P. Clinical use of circulating nucleosomes. Crit Rev Clin Lab Sci. 2009;46(1):1–24.Google Scholar
  13. 13.
    Holdenrieder S, Burges A, Reich O, Spelsberg FW, Stieber P. DNA integrity in plasma and serum of patients with malignant and benign diseases. Ann N Y Acad Sci. 2008;1137:162–70.Google Scholar
  14. 14.
    Sunami E, Vu AT, Nguyen SL, Giuliano AE, Hoon DS. Quantification of LINE1 in circulating DNA as a molecular biomarker of breast cancer. Ann N Y Acad Sci. 2008;1137:171–4.Google Scholar
  15. 15.
    Gal S, Fidler C, Lo YM, Taylor M, Han C, Moore J, et al. Quantitation of circulating DNA in the serum of breast cancer patients by real-time PCR. Br J Cancer. 2004;90(6):1211–5.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Silva JM, Silva J, Sanchez A, Garcia JM, Dominguez G, Provencio M, et al. Tumor DNA in plasma at diagnosis of breast cancer patients is a valuable predictor of disease-free survival. Clin Cancer Res. 2002;8(12):3761–6.PubMedGoogle Scholar
  17. 17.
    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
  18. 18.
    Gu Z, Wang H, Nekrutenko A, Li WH. Densities, length proportions, and other distributional features of repetitive sequences in the human genome estimated from 430 megabases of genomic sequence. Gene. 2000;259(1–2):81–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Giacona MB, Ruben GC, Iczkowski KA, Roos TB, Porter DM, Sorenson GD. Cell-free DNA in human blood plasma: length measurements in patients with pancreatic cancer and healthy controls. Pancreas. 1998;17(1):89–97.PubMedCrossRefGoogle Scholar
  20. 20.
    Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch RD, et al. DNA fragments in the blood plasma of cancer patients: Quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 2001;61(4):1659–65.PubMedGoogle Scholar
  21. 21.
    Jin Z, El-Deiry WS. Overview of cell death signaling pathways. Cancer Biol Ther. 2005;4(2):139–63.PubMedCrossRefGoogle Scholar
  22. 22.
    Wang BG, Huang HY, Chen YC, Bristow RE, Kassauei K, Cheng CC, et al. Increased plasma DNA integrity in cancer patients. Cancer Res. 2003;63(14):3966–8.PubMedGoogle Scholar
  23. 23.
    Ellinger J, Wittkamp V, Albers P, Perabo FG, Mueller SC, von Ruecker A, et al. Cell-free circulating DNA: Diagnostic value in patients with testicular germ cell cancer. J Urol. 2009;181(1):363–71.Google Scholar
  24. 24.
    Holdenrieder S, Stieber P, von Pawel J, Raith H, Nagel D, Feldmann K, et al. Circulating nucleosomes predict the response to chemotherapy in patients with advanced non-small cell lung cancer. Clin Cancer Res. 2004;10(18 Pt 1):5981–7.Google Scholar
  25. 25.
    Kohler C, Radpour R, Barekati Z, Asadollahi R, Bitzer J, Wight E, et al. Levels of plasma circulating cell free nuclear and mitochondrial DNA as potential biomarkers for breast tumors. Mol Cancer. 2009;8:105.Google Scholar
  26. 26.
    Catarino R, Ferreira MM, Rodrigues H, Coelho A, Nogal A, Sousa A, et al. Quantification of free circulating tumor DNA as a diagnostic marker for breast cancer. DNA Cell Biol. 2008;27(8):415–21.Google Scholar
  27. 27.
    Jung K, Fleischhacker M, Rabien A. Cell-free DNA in the blood as a solid tumor biomarker—a critical appraisal of the literature. Clin Chim Acta. 2010;411(21–22):1611–24.Google Scholar
  28. 28.
    Boddy JL, Gal S, Malone PR, Shaida N, Wainscoat JS, Harris AL. The role of cell-free DNA size distribution in the management of prostate cancer. Oncol Res. 2006;16(1):35–41.PubMedGoogle Scholar
  29. 29.
    Schmidt B, Weickmann S, Witt C, Fleischhacker M. Integrity of cell-free plasma DNA in patients with lung cancer and nonmalignant lung disease. Ann N Y Acad Sci. 2008;1137:207–13.Google Scholar
  30. 30.
    Chang HW, Lee SM, Goodman SN, Singer G, Cho SK, Sokoll LJ, et al. Assessment of plasma DNA levels, allelic imbalance, and CA 125 as diagnostic tests for cancer. J Natl Cancer Inst. 2002;94(22):1697–703.PubMedCrossRefGoogle Scholar
  31. 31.
    de Kok JB, Hendriks JC, van Solinge WW, Willems HL, Mensink EJ, Swinkels DW. Use of real-time quantitative PCR to compare DNA isolation methods. Clin Chem. 1998;44(10):2201–4.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Oliver J. Stötzer
    • 1
  • Julia Lehner
    • 2
  • Debora Fersching-Gierlich
    • 2
  • Dorothea Nagel
    • 2
  • Stefan Holdenrieder
    • 3
  1. 1.Hematology/Oncology Outpatient Centre MunichMunichGermany
  2. 2.Institute of Clinical ChemistryUniversity Hospital Munich-GrosshadernMunichGermany
  3. 3.Institute of Clinical Chemistry and Clinical PharmacologyUniversity Hospital BonnBonnGermany

Personalised recommendations