Skip to main content

Advertisement

SpringerLink
Log in

Prognostic Value of TOP2A Gene Amplification and Chromosome 17 Polysomy in Early Breast Cancer

  • Research
  • Published:
Pathology & Oncology Research

Abstract

The aim of this study was to analyze the occurrence of TOP2A gene amplification and chromosome 17 polysomy in patients with early breast cancer and to correlate the status of these alterations with the prognostic significance expressed as patients’ clinical features and survival. Such concurrent analyses of TOP2A gene status and chromosome 17 polysomy have not been performed before. Study group included 149 consecutive stage I-III patients administered standard multimodality treatment. TOP2A abnormalities were examined by standard fluorescence in situ hybridization (FISH) and developed by our group quantitative real-time PCR (qPCR). TOP2A amplification and deletion assessed by FISH were found in 23% and 7% of the tumours, respectively, and by qPCR in 31% and 11% of the tumours, respectively. Chromosome 17 polysomy was detected in 40% of the cases. TOP2A amplification (by qPCR) correlated with shorter disease-free survival (p = 0.03) and overall survival (p = 0.047), and the prognostic value of TOP2A was confirmed in the multivariate analysis (HR = 3.22, 95% CI 1.09–9.56, p = 0.03). TOP2A gene amplification, but not chromosome 17 polysomy, carries negative prognostic information in early breast cancer. Given the aforementioned results, qPCR might serve as a prognostic tool in determining the patient’s prognosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Lehmann U, Glöckner S, Kleeberger W, Feist H, Rv W, Kreipe H (2000) Detection of gene amplification in archival breast cancer specimens by laser-assisted microdissection and quantitative real-time polymerase chain reaction. Am J Pathol 156(6):1855–1864

    Article  PubMed  CAS  Google Scholar 

  2. Mano MS, Rosa DD, Azambuja ED, Ismael GFV, Durbecq V (2007) The 17q12-q21 amplicon: Her2 and topoisomerase-IIa and their importance to the biology of solid tumours. Cancer Treat Rev 33:64–77

    Article  PubMed  CAS  Google Scholar 

  3. Park K, Kim J, Lim S, Han S (2003) Topoisomerase II-alpha (topoII) and HER2 amplification in breast cancers and response to preoperative doxorubicin chemotherapy. Eur J Cancer 39(5):631–634. doi:S0959804902007451

    Article  PubMed  CAS  Google Scholar 

  4. Järvinen TAH, Liu ET (2003) HER-2/neu and topoisomerase IIα in breast cancer. Breast Cancer Res Treat 78:299–311

    Article  PubMed  Google Scholar 

  5. Durbecq V, Paesmans M, Cardoso F, Desmedt C, Di Leo A, Chan S, Friedrichs K, Pinter T, Van Belle S, Murray E, Bodrogi I, Walpole E, Lesperance B, Korec S, Crown J, Simmonds P, Perren TJ, Leroy JY, Rouas G, Sotiriou C, Piccart M, Larsimont D (2004) Topoisomerase-II alpha expression as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel. Mol Cancer Ther 3(10):1207–1214. doi:3/10/1207

    PubMed  CAS  Google Scholar 

  6. O’Malley FP, Chia S, Tu D, Shepherd LE, Levine MN, Bramwell VH, Andrulis IL, Pritchard KI (2009) Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst 101(9):644–650. doi:djp067

    Article  PubMed  Google Scholar 

  7. Arriola E, Maria S, Rodriguez-Pinilla LMBK, Jones RL, James M, Savage K, Smith IE, Dowsett M, Reis-Filho JS (2007) Topoisomerase II alpha amplification may predict benefit from adjuvant anthracyclines in HER2 positive early breast cancer. Breast Cancer Res Treat 106:181–189

    Article  PubMed  CAS  Google Scholar 

  8. Knoop AS, Knudsen H, Balslev E, Rasmussen BB, Overgaard J, Nielsen KV, Schonau A, Gunnarsdottir K, Olsen KE, Mouridsen H, Ejlertsen B (2005) Retrospective analysis of Topoisomerase IIa amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to Cyclophosphamide, Methotrexate, and Fluorouracil or Cyclophosphamide, Epirubicin, and Fluorouracil: Danish Breast Cancer Cooperative Group. J Clin Oncol 23(20):7483–7490

    Article  PubMed  CAS  Google Scholar 

  9. Nielsen KV, Ejlertsen B, Moller S, Jorgensen JT, Knoop A, Knudsen H, Mouridsen HT (2008) The value of TOP2A gene copy number variation as a biomarker in breast cancer: update of DBCG trial 89D. Acta Oncol 47(4):725–734. doi:791851530

    Article  PubMed  CAS  Google Scholar 

  10. Park K, Han S, Gwak GH, Kim HJ, Kim J, Kim KM (2006) Topoisomerase II-alpha gene deletion is not frequent as its amplification in breast cancer. Breast Cancer Res Treat 98(3):337–342. doi:10.1007/s10549-006-9170-7

    Article  PubMed  CAS  Google Scholar 

  11. Shackney SE, Singh SG, Yakulis R, Smith CA, Pollice AA, Petruolo S, Waggoner A, Hartsock RJ (1995) Aneuploidy in breast cancer: a fluorescence in situ hybridization study. Cytometry 22(4):282–291. doi:10.1002/cyto.990220404

    Article  PubMed  CAS  Google Scholar 

  12. Staaf J, Jonsson G, Ringner M, Vallon-Christersson J, Grabau D, Arason A, Gunnarsson H, Agnarsson BA, Malmstrom PO, Johannsson OT, Loman N, Barkardottir RB, Borg A (2010) High-resolution genomic and expression analyses of copy number alterations in HER2-amplified breast cancer. Breast Cancer Res 12(3):R25. doi:bcr2568

    Article  PubMed  Google Scholar 

  13. Gunn S, Yeh IT, Lytvak I, Tirtorahardjo B, Dzidic N, Zadeh S, Kim J, McCaskill C, Lim L, Gorre M, Mohammed M (2010) Clinical array-based karyotyping of breast cancer with equivocal HER2 status resolves gene copy number and reveals chromosome 17 complexity. BMC Cancer 10:396. doi:1471-2407-10-396

    Article  PubMed  Google Scholar 

  14. Moelans CB, de Weger RA, van Diest PJ (2009) Absence of chromosome 17 polysomy in breast cancer: analysis by CEP17 chromogenic in situ hybridization and multiplex ligation-dependent probe amplification. Breast Cancer Res Treat 120(1):1–7. doi:10.1007/s10549-009-0539-2

    Article  PubMed  Google Scholar 

  15. Reinholz MM, Bruzek AK, Visscher DW, Lingle WL, Schroeder MJ, Perez EA, Jenkins RB (2009) Breast cancer and aneusomy 17: implications for carcinogenesis and therapeutic response. Lancet Oncol 10(3):267–277. doi:S1470-2045(09)70063-4

    Article  PubMed  CAS  Google Scholar 

  16. Krishnamurti U, Hammers JL, Atem FD, Storto PD, Silverman JF (2009) Poor prognostic significance of unamplified chromosome 17 polysomy in invasive breast carcinoma. Mod Pathol 22(8):1044–1048. doi:modpathol200961

    Article  PubMed  CAS  Google Scholar 

  17. Watters AD, Going JJ, Cooke TG, Bartlett JM (2003) Chromosome 17 aneusomy is associated with poor prognostic factors in invasive breast carcinoma. Breast Cancer Res Treat 77(2):109–114

    Article  PubMed  CAS  Google Scholar 

  18. Vanden Bempt I, Van Loo P, Drijkoningen M, Neven P, Smeets A, Christiaens MR, Paridaens R, De Wolf-Peeters C (2008) Polysomy 17 in breast cancer: clinicopathologic significance and impact on HER-2 testing. J Clin Oncol 26(30):4869–4874. doi:JCO.2007.13.4296

    Article  PubMed  Google Scholar 

  19. Torrisi R, Rotmensz N, Bagnardi V, Viale G, Curto BD, Dell’orto P, Veronesi P, Luini A, D’Alessandro C, Cardillo A, Goldhirsch A, Colleoni M (2007) HER2 status in early breast cancer: relevance of cell staining patterns, gene amplification and polysomy 17. Eur J Cancer 43(16):2339–2344. doi:S0959-8049(07)00560-6

    Article  PubMed  CAS  Google Scholar 

  20. Järvinen T, Tanner M, Rantanen V, Bärlund M, Borg Å, Grènman S (2000) Amplification and deletion of topoisomerase IIa associate with ErbB-2 amplification and affect sensitivity to topoisomerase II Inhibitor doxorubicin in breast cancer. Am J Pathol 156:839–847

    Article  PubMed  Google Scholar 

  21. Zaczek A, Markiewicz A, Jaskiewicz J, Pienkowski T, Rhone P, Jassem J, Welnicka-Jaskiewicz M (2010) Clinical evaluation of developed PCR-based method with hydrolysis probes for TOP2A copy number evaluation in breast cancer samples. Clin Biochem 43(10–11):891–898. doi:S0009-9120(10)00193-1

    Article  PubMed  CAS  Google Scholar 

  22. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer 93(4):387–391. doi:6602678

    Article  PubMed  CAS  Google Scholar 

  23. Romero A, Martín M, Cheang MC, López García-Asenjo JA, Oliva B, He X, de la Hoya M, García Sáenz J, Arroyo Fernández M, Díaz Rubio E, Perou CM, Llopis TC (2011) Assessment of Topoisomerase II α status in breast cancer by quantitative PCR, gene expression microarrays, immunohistochemistry, and fluorescence in situ hybridization. Am J Pathol 178(4):1453–1460. doi:S0002-9440(11)00042-3

    Article  PubMed  Google Scholar 

  24. Hicks DG, Yoder BJ, Pettay J, Swain E, Tarr S, Hartke M, Skacel M, Crowe JP, Budd T, Tubbs RR (2004) The incidence of topoisomerase II-alpha genomic alterations in adenocarcinoma of the breast and their relationship to human epidermal growth factor receptor-2 gene amplification: A fluorescence in situ hybridization study. Hum Pathol 36(4):348–356

    Article  Google Scholar 

  25. Di Leo A, Gancberg D, Larsimont D, Tanner M, Jarvinen T, Rouas G, Dolci S, Leroy JY, Paesmans M, Isola J, Piccart MJ (2002) HER-2 amplification and topoisomerase IIalpha gene aberrations as predictive markers in node-positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil. Clin Cancer Res 8(5):1107–1116

    PubMed  Google Scholar 

  26. Konecny GE, Pauletti G, Untch M, Wang HJ, Mobus V, Kuhn W, Thomssen C, Harbeck N, Wang L, Apple S, Janicke F, Slamon DJ (2010) Association between HER2, TOP2A, and response to anthracycline-based preoperative chemotherapy in high-risk primary breast cancer. Breast Cancer Res Treat 120(2):481–489. doi:10.1007/s10549-010-0744-z

    Article  PubMed  CAS  Google Scholar 

  27. Slamon DJ, Press MF (2009) Alterations in the TOP2A and HER2 genes: association with adjuvant anthracycline sensitivity in human breast cancers. J Natl Cancer Inst 101(9):615–618. doi:djp092

    Article  PubMed  CAS  Google Scholar 

  28. Herrington CS, Leek RD, McGee JO (1995) Correlation of numerical chromosome 11 and 17 imbalance with metastasis of primary breast cancer to lymph nodes. J Pathol 176(4):353–359. doi:10.1002/path.1711760406

    Article  PubMed  CAS  Google Scholar 

  29. Ichikawa D, Hashimoto N, Hoshima M, Yamaguchi T, Sawai K, Nakamura Y, Takahashi T, Abe T, Inazawa J (1996) Analysis of numerical aberrations of specific chromosomes by fluorescent in situ hybridization as a diagnostic tool in breast cancer. Cancer 77(10):2064–2069. doi:10.1002/(SICI)1097-0142(19960515)77:10<2064::AID-CNCR15>3.0.CO;2-T

    Article  PubMed  CAS  Google Scholar 

  30. McManus DT, Patterson AH, Maxwell P, Hamilton PW, Anderson NH, Caughley LM, Toner PG (1999) Interphase cytogenetics of chromosomes 11 and 17 in fine needle aspirates of breast cancer. Hum Pathol 30(2):137–144

    Article  PubMed  CAS  Google Scholar 

  31. Tsukamoto F, Miyoshi Y, Egawa C, Kasugai T, Takami S, Inazawa J, Noguchi S (2001) Clinicopathologic analysis of breast carcinoma with chromosomal aneusomy detected by fluorescence in situ hybridization. Cancer 93(2):165–170

    Article  PubMed  CAS  Google Scholar 

  32. Fehm T, Morrison L, Saboorian H, Hynan L, Tucker T, Uhr J (2002) Patterns of aneusomy for three chromosomes in individual cells from breast cancer tumors. Breast Cancer Res Treat 75(3):227–239

    Article  PubMed  CAS  Google Scholar 

  33. Nakopoulou L, Giannopoulou I, Trafalis D, Gakiopoulou H, Keramopoulos A, Davaris P (2002) Evaluation of numeric alterations of chromosomes 1 and 17 by in situ hybridization in invasive breast carcinoma with clinicopathologic parameters. Appl Immunohistochem Mol Morphol 10(1):20–28

    Article  PubMed  Google Scholar 

  34. Wang S, Hossein Saboorian M, Frenkel EP, Haley BB, Siddiqui MT, Gokaslan S, Hynan L, Ashfaq R (2002) Aneusomy 17 in breast cancer: its role in HER-2/neu protein expression and implication for clinical assessment of HER-2/neu status. Mod Pathol 15(2):137–145. doi:10.1038/modpathol.3880505

    Article  PubMed  Google Scholar 

  35. Ma Y, Lespagnard L, Durbecq V, Paesmans M, Desmedt C, Gomez-Galdon M, Veys I, Cardoso F, Sotiriou C, Di Leo A, Piccart MJ, Larsimont D (2005) Polysomy 17 in HER-2/neu status elaboration in breast cancer: effect on daily practice. Clin Cancer Res 11(12):4393–4399. doi:11/12/4393

    Article  PubMed  CAS  Google Scholar 

  36. Merola R, Mottolese M, Orlandi G, Vico E, Cognetti F, Sperduti I, Fabi A, Vitelli G, Cianciulli AM (2006) Analysis of aneusomy level and HER-2 gene copy number and their effect on amplification rate in breast cancer specimens read as 2+ in immunohistochemical analysis. Eur J Cancer 42(10):1501–1506. doi:S0959-8049(06)00319-4

    Article  PubMed  CAS  Google Scholar 

  37. Dowsett M, Hanna WM, Kockx M, Penault-Llorca F, Ruschoff J, Gutjahr T, Habben K, van de Vijver MJ (2007) Standardization of HER2 testing: results of an international proficiency-testing ring study. Mod Pathol 20(5):584–591. doi:3800774

    Article  PubMed  Google Scholar 

  38. Marchio C, Lambros MB, Gugliotta P, Di Cantogno LV, Botta C, Pasini B, Tan DS, Mackay A, Fenwick K, Tamber N, Bussolati G, Ashworth A, Reis-Filho JS, Sapino A (2009) Does chromosome 17 centromere copy number predict polysomy in breast cancer? A fluorescence in situ hybridization and microarray-based CGH analysis. J Pathol 219(1):16–24. doi:10.1002/path.2574

    Article  PubMed  CAS  Google Scholar 

  39. Beser AR, Tuzlali S, Guzey D, Dolek Guler S, Hacihanefioglu S, Dalay N (2007) HER-2, TOP2A and chromosome 17 alterations in breast cancer. Pathol Oncol Res 13(3):180–185. doi:PAOR.2007.13.3.0180

    Article  PubMed  Google Scholar 

  40. Järvinen TA, Tanner M, Bärlund M, Borg A, Isola J (1999) Characterization of topoisomerase II alpha gene amplification and deletion in breast cancer. Genes Chromosomes Cancer 26(2):142–150. doi:10.1002/(SICI)1098-2264(199910)26:2<142::AID-GCC6>3.0.CO;2-B

    Article  PubMed  Google Scholar 

  41. Brase JC, Schmidt M, Fischbach T, Sultmann H, Bojar H, Koelbl H, Hellwig B, Rahnenfuhrer J, Hengstler JG, Gehrmann MC (2010) ERBB2 and TOP2A in breast cancer: a comprehensive analysis of gene amplification, RNA levels, and protein expression and their influence on prognosis and prediction. Clin Cancer Res 16(8):2391–2401. doi:1078-0432.CCR-09-2471

    Article  PubMed  CAS  Google Scholar 

  42. Bartlett JM, Munro AF, Dunn JA, McConkey C, Jordan S, Twelves CJ, Cameron DA, Thomas J, Campbell FM, Rea DW, Provenzano E, Caldas C, Pharoah P, Hiller L, Earl H, Poole CJ (2010) Predictive markers of anthracycline benefit: a prospectively planned analysis of the UK National Epirubicin Adjuvant Trial (NEAT/BR9601). Lancet Oncol 11(3):266–274. doi:S1470-2045(10)70006-1

    Article  PubMed  CAS  Google Scholar 

  43. Downey L, Livingston RB, Koehler M, Arbushites M, Williams L, Santiago A, Guzman R, Villalobos I, Di Leo A, Press MF (2010) Chromosome 17 polysomy without human epidermal growth factor receptor 2 amplification does not predict response to lapatinib plus paclitaxel compared with paclitaxel in metastatic breast cancer. Clin Cancer Res 16(4):1281–1288. doi:1078-0432.CCR-09-1643

    Article  PubMed  CAS  Google Scholar 

  44. Bartlett JMS, Munro A, Cameron DA, Thomas J, Prescott R, Twelves CJ (2008) Type 1 receptor tyrosine kinase profiles identify patients with enhanced benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial. J Clin Oncol 28(31)

  45. Glynn RW, Miller N, Whelan MC, Kerin MJ (2010) Topoisomerase 2 alpha and the case for individualized breast cancer therapy. Ann Surg Oncol 17(5):1392–1397. doi:10.1245/s10434-009-0855-0

    Article  PubMed  Google Scholar 

  46. Bednarz N, Eltze E, Semjonow A, Rink M, Andreas A, Mulder L, Hannemann J, Fisch M, Pantel K, Weier HU, Bielawski KP, Brandt B (2010) BRCA1 loss preexisting in small subpopulations of prostate cancer is associated with advanced disease and metastatic spread to lymph nodes and peripheral blood. Clin Cancer Res 16(13):3340–3348. doi:1078-0432.CCR-10-0150

    Article  PubMed  CAS  Google Scholar 

  47. Salido M, Tusquets I, Corominas JM, Suarez M, Espinet B, Corzo C, Bellet M, Fabregat X, Serrano S, Sole F (2005) Polysomy of chromosome 17 in breast cancer tumors showing an overexpression of ERBB2: a study of 175 cases using fluorescence in situ hybridization and immunohistochemistry. Breast Cancer Res 7(2):R267–273. doi:bcr996

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by grants from Ministry of Science and Higher Education: N N401 2334 33 and IP2010 050370.

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Laboratory of Cell Biology, Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Dębinki 1, 80-211, Gdańsk, Poland

    Anna Żaczek, Aleksandra Markiewicz & Anna Supernat

  2. Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland

    Aleksandra Markiewicz

  3. Institute of Tumour Biology, University Medical Centre, Hamburg-Eppendorf, Martinistrasse 52, 20-246, Hamburg, Germany

    Natalia Bednarz-Knoll & Burkhardt Brandt

  4. Bank of Frozen Tissues and Genetic Specimen, Medical University of Gdańsk, Dębinki 1, 80-211, Gdańsk, Poland

    Barbara Seroczyńska & Jarosław Skokowski

  5. Department of Pathomorphology, Medical University of Gdańsk, Dębinki 7, 80-211, Gdańsk, Poland

    Jolanta Szade, Piotr Czapiewski & Wojciech Biernat

  6. Department of Oncology and Radiotherapy, Medical University of Gdańsk, Dębinki 7, 80-211, Gdańsk, Poland

    Marzena Wełnicka-Jaśkiewicz & Jacek Jassem

Authors
  1. Anna Żaczek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aleksandra Markiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Supernat
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Natalia Bednarz-Knoll
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Burkhardt Brandt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Barbara Seroczyńska
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jarosław Skokowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jolanta Szade
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Piotr Czapiewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wojciech Biernat
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Marzena Wełnicka-Jaśkiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jacek Jassem
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anna Żaczek.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Żaczek, A., Markiewicz, A., Supernat, A. et al. Prognostic Value of TOP2A Gene Amplification and Chromosome 17 Polysomy in Early Breast Cancer. Pathol. Oncol. Res. 18, 885–894 (2012). https://doi.org/10.1007/s12253-012-9518-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-012-9518-8

Keywords

Search

Navigation