Pathology & Oncology Research

, Volume 24, Issue 3, pp 575–581 | Cite as

HER2 and TOP2A Gene Amplification and Protein Expression in Upper Tract Urothelial Carcinomas

  • Klaus Aumayr
  • Tobias Klatte
  • Barbara Neudert
  • Peter Birner
  • Shahrokh Shariat
  • Manuela Schmidinger
  • Martin Susani
  • Andrea HaitelEmail author
Original Article


HER2, a potential target for therapy, has been described to be amplified in urothelial carcinomas. As the topoisomerase II alpha (TOP2A) gene is located close to the HER2 gene on chromosome 17q12-q21, it is frequently either co-amplified or deleted with HER2 amplification. The purpose of this study was to assess the impact HER2 and TOP2A gene amplification as well as protein expression on outcomes of upper tract urothelial carcinoma (UTUC). HER2 and TOP2A gene amplification and protein expression were assessed in 81 patients with radical nephroureterectomy for UTUC. Immunohistochemistry and chromogenic in-situ hybridization was performed on formalin-fixed, paraffin-embedded samples. HER2 protein expression was observed in 27/81 (33%) cases, of which 8 cases exhibited amplification of HER2. One of them had an additional polysomy 17, whereas 6/67 HER2 non-amplified cases revealed a polysomy 17. Coamplification of HER2 and TOP2A was found in 4 cases, whereas 3 cases showed only HER2 amplification and 20 cases only TOP2A amplification. HER2 IHC overexpression was associated with higher-grade tumors (p = 0.001), non-organ confined carcinomas (p = 0.017), HER2 amplification (p < 0.00001) and TOP2A amplification (p = 0.016). HER2 amplification was association with higher tumor grade (p = 0.001) and lymphnode metastasis (p = 0.003). TOP2A IHC positivity was significantly associated with higher tumor grade (p = 0.0004), TOP2A amplification (p = 0.0003), polysomy 17 (p = 0.035) and HER2 IHC overexpression (p = 0.28), whereas all categories of tumor stage and HER2 amplification remained not related. TOP2A amplification was significantly more frequent in tumors with higher grade, higher tumor stage, polysomy 17 and distant metastasis (p = 0.015; p = 0.042; p = 0.032; p = 0.011), respectively. In univariate analyses HER2 IHC positivity, TOP2A amplification, and polysomy 17 were associated with poor clinical outcome after surgery. HER2 IHC overexpression and TOP2A amplification are associated with features of biologically aggressive UTUC. Overexpression and/or amplification of HER2 and TOP2A could help identify patients who may benefit from targeted therapy.


HER2 TOP2A Polysomy 17 Amplification Anthracyclines Urothelial carcinoma 


Author Contributions

Information on how each individual author contributed to the original article:

1. Conception and design, or analysis and interpretation of data: Klaus Aumayr, Andrea Haitel.

2. Analysis of data: Barbara Neudert.

3. Drafting the article: Klaus Aumayr.

4. Revising it critically for important intellectual content: Tobias Klatte, Peter Birner, Shahrokh Shariat, Manuela Schmidinger, Martin Susani.

5. Guarantor for the article: Andrea Haitel.


  1. 1.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353(16):1659–1672CrossRefPubMedGoogle Scholar
  2. 2.
    Burstein HJ (2005) The distinctive nature of HER2-positive breast cancers. N Engl J Med 353(16):1652–1654CrossRefPubMedGoogle Scholar
  3. 3.
    Hortobagyi GN (2005) Trastuzumab in the treatment of breast cancer. N Engl J Med 353(16):1734–1736CrossRefPubMedGoogle Scholar
  4. 4.
    Eisenhauer EA (2001) From the molecule to the clinic--inhibiting HER2 to treat breast cancer. N Engl J Med 344(11):841–842CrossRefPubMedGoogle Scholar
  5. 5.
    Nielsen DL, Andersson M, Kamby C (2009) HER2-targeted therapy in breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors. Cancer Treat Rev 35(2):121–136CrossRefPubMedGoogle Scholar
  6. 6.
    Yan M, Parker BA, Schwab R, Kurzrock R (2014) HER2 aberrations in cancer: implications for therapy. Cancer Treat Rev 40(6):770–780CrossRefPubMedGoogle Scholar
  7. 7.
    Bolenz C, Shariat SF, Karakiewicz PI, Ashfaq R, Ho R, Sagalowsky AI et al (2010) Human epidermal growth factor receptor 2 expression status provides independent prognostic information in patients with urothelial carcinoma of the urinary bladder. BJU Int 106(8):1216–1222CrossRefPubMedGoogle Scholar
  8. 8.
    Rink M, Chun FK, Dahlem R, Soave A, Minner S, Hansen J et al (2012) Prognostic role and HER2 expression of circulating tumor cells in peripheral blood of patients prior to radical cystectomy: a prospective study. Eur Urol 61(4):810–817CrossRefPubMedGoogle Scholar
  9. 9.
    Bast R, Ravdin P, Hayes D, Bates S, Fritsche H, Jessup J et al (2001) 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 19(6):1865–1878CrossRefPubMedGoogle Scholar
  10. 10.
    Durbecq V, Paesmans M, Cardoso F, Desmedt C, Di Leo A, Chan S et al (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):1207–1214PubMedGoogle Scholar
  11. 11.
    Pegram M, Hsu S, Lewis G, Pietras R, Beryt M, Sliwkowski M et al (1999) Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene 18(13):2241–2251CrossRefPubMedGoogle Scholar
  12. 12.
    Pritchard KI, Messersmith H, Elavathil L, Trudeau M, O'Malley F, Dhesy-Thind B (2008) HER-2 and topoisomerase II as predictors of response to chemotherapy. J Clin Oncol 26(5):736–744CrossRefPubMedGoogle Scholar
  13. 13.
    Ethikkommission-MUW. HER2 and TOP2A Genamplifikation und Protein Expression in Urothelzellkarzinomen des oberes Traktes - eine retrospektive Analyse. EK Nr: 1094/2016Google Scholar
  14. 14.
    Bjerkehagen B, Fosså SD, Raabe N, Holm R, Nesland JM (1994) Transitional cell carcinoma of the renal pelvis and its expression of p53 protein, c-erbB-2 protein, neuron-specific enolase, Phe 5, chromogranin, laminin and collagen type IV. Eur Urol 26(4):334–339CrossRefPubMedGoogle Scholar
  15. 15.
    Corzo C, Bellosillo B, Corominas JM, Salido M, Coll MD, Serrano S et al (2007) Does polysomy of chromosome 17 have a role in ERBB2 and topoisomerase IIalpha expression? Gene, mRNA and protein expression: a comprehensive analysis. Tumour Biol 28(4):221–228CrossRefPubMedGoogle Scholar
  16. 16.
    Nitiss JL. Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer 2009;9(5):338–350Google Scholar
  17. 17.
    Sobin L, Gospodarowicz M, Wittekind C (2009) TNM classification of malignant tumours. Vol 7th editionGoogle Scholar
  18. 18.
    Sasaki Y, Sasaki T, Kawai T, Morikawa T, Matsusaka K, Kunita A et al (2014) HER2 protein overexpression and gene amplification in upper urinary tract urothelial carcinoma-an analysis of 171 patients. Int J Clin Exp Pathol 7(2):699–708PubMedPubMedCentralGoogle Scholar
  19. 19.
    Grivas PD, Day M, Hussain M (2011) Urothelial carcinomas: a focus on human epidermal receptors signaling. Am J Transl Res 3(4):362–373PubMedPubMedCentralGoogle Scholar
  20. 20.
    Vershasselt-Crinquette M, Colin P, Ouzzane A, Gnemmi V, Robin Y-M, Aubert S et al (2012) Assessment of human epidermal growth factor receptor 2 status in urothelial carcinoma of the upper urinary tract: a study using dual-color in situ hybridization and immunohistochemistry. Appl Immunohistochem Mol Morphol 20(4):363–366CrossRefPubMedGoogle Scholar
  21. 21.
    Tsai Y-S, Tzai T-S, Chow N-H, Wu C-L (2005) Frequency and clinicopathologic correlates of ErbB1, ErbB2, and ErbB3 immunoreactivity in urothelial tumors of upper urinary tract. Urology 66(6):1197–1202CrossRefPubMedGoogle Scholar
  22. 22.
    Imai T, Kimura M, Takeda M, Tomita Y (1995) Significance of epidermal growth factor receptor and c-erbB-2 protein expression in transitional cell cancer of the upper urinary tract for tumour recurrence at the urinary bladder. Br J Cancer 71(1):69–72CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Langner C, Gross C, Rehak P, Ratschek M, Rüschoff J, Zigeuner R (2005) HER2 protein overexpression and gene amplification in upper urinary tract transitional cell carcinoma: systematic analysis applying tissue microarray technique. Urology 65(1):176–180CrossRefPubMedGoogle Scholar
  24. 24.
    Tsai Y-S, Tzai T-S, Chow N-H (2007) Does HER2 immunoreactivity provide prognostic information in locally advanced urothelial carcinoma patients receiving adjuvant M-VEC chemotherapy? Urol Int 79(3):210–216CrossRefPubMedGoogle Scholar
  25. 25.
    Ehsani L, Osunkoya AO (2014) Human epidermal growth factor receptor 2 expression in urothelial carcinoma of the renal pelvis: correlation with clinicopathologic parameters. Int J Clin Exp Pathol 7(5):2544–2550PubMedPubMedCentralGoogle Scholar
  26. 26.
    Nakopoulou L, Zervas A, Lazaris AC, Constantinides C, Stravodimos C, Davaris P et al (2001) Predictive value of topoisomerase II alpha immunostaining in urothelial bladder carcinoma. J Clin Pathol 54(4):309–313CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Fleischmann A, Rotzer D, Seiler R, Studer UE, Thalmann GN (2011) Her2 amplification is significantly more frequent in lymph node metastases from urothelial bladder cancer than in the primary tumours. Eur Urol 60(2):350–357CrossRefPubMedGoogle Scholar
  28. 28.
    Hofmann M, Stoss O, Shi D, Büttner R, van de Vijver M, Kim W et al (2008) Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 52(7):797–805CrossRefPubMedGoogle Scholar
  29. 29.
    Ben Abdelkrim S, Rammeh S, Ziadi S, Tlili T, Jaidane M, Mokni M (2014) Expression of topoisomerase II alpha, ki67, and p53 in primary non-muscle-invasive urothelial bladder carcinoma. J Immunoass Immunochem 35(4):358–367CrossRefGoogle Scholar
  30. 30.
    Koren R, Kugel V, Dekel Y, Weissman Y, Livne PM, Gal R (2003) Human DNA topoisomerase-IIalpha expression as a prognostic factor for transitional cell carcinoma of the urinary bladder. BJU Int 91(6):489–492CrossRefPubMedGoogle Scholar
  31. 31.
    Raspollini MR, Minervini A, Lapini A, Lanzi F, Rotellini M, Baroni G et al (2013) A proposed score for assessing progression in pT1 high-grade urothelial carcinoma of the bladder. Appl Immunohistochem Mol Morphol 21(3):218–227PubMedGoogle Scholar
  32. 32.
    Roupret M, Zigeuner R, Palou J, Boehle A, Kaasinen E, Sylvester R et al (2011) European guidelines for the diagnosis and Management of Upper Urinary Tract Urothelial Cell Carcinomas: 2011 update. Eur Urol 59(4):584–594CrossRefPubMedGoogle Scholar
  33. 33.
    Simonetti S, Russo R, Ciancia G, Altieri V, De Rosa G, Insabato L (2009) Role of polysomy 17 in transitional cell carcinoma of the bladder: immunohistochemical study of HER2/neu expression and fish analysis of c-erbB-2 gene and chromosome 17. Int J Surg Pathol 17(3):198–205CrossRefPubMedGoogle Scholar
  34. 34.
    Ching CB, Amin MB, Tubbs RR, Elson P, Platt E, Dreicer R et al (2011) HER2 gene amplification occurs frequently in the micropapillary variant of urothelial carcinoma: analysis by dual-color in situ hybridization. Mod Pathol 24(8):1111–1119CrossRefPubMedGoogle Scholar
  35. 35.
    Gunia S, Koch S, Hakenberg OW, May M, Kakies C, Erbersdobler A (2011) Different HER2 protein expression profiles aid in the histologic differential diagnosis between urothelial carcinoma in situ (CIS) and non-CIS conditions (dysplasia and reactive atypia) of the urinary bladder mucosa. Am J Clin Pathol 136(6):881–888CrossRefPubMedGoogle Scholar
  36. 36.
    Olsson H, Fyhr I-M, Hultman P, Jahnson S (2012) HER2 status in primary stage T1 urothelial cell carcinoma of the urinary bladder. Scand J Urol Nephrol 46(2):102–107CrossRefPubMedGoogle Scholar
  37. 37.
    Laé M, Couturier J, Oudard S, Radvanyi F, Beuzeboc P, Vieillefond A (2010) Assessing HER2 gene amplification as a potential target for therapy in invasive urothelial bladder cancer with a standardized methodology: results in 1005 patients. Ann Oncol 21(4):815–819CrossRefPubMedGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2017

Authors and Affiliations

  • Klaus Aumayr
    • 1
  • Tobias Klatte
    • 2
  • Barbara Neudert
    • 1
  • Peter Birner
    • 1
  • Shahrokh Shariat
    • 2
  • Manuela Schmidinger
    • 3
  • Martin Susani
    • 1
  • Andrea Haitel
    • 1
    Email author
  1. 1.Department of PathologyMedical University of ViennaViennaAustria
  2. 2.Department of UrologyMedical University of ViennaViennaAustria
  3. 3.Department of Internal MedicineMedical University of ViennaViennaAustria

Personalised recommendations