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Topoisomerase II-alpha gene deletion is not frequent as its amplification in breast cancer

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Summary

Topoisomerase II-alpha (TOP2A) has been investigated as a potential predictor for the response to doxorubicin-based chemotherapy which is a representative TOP2A inhibitor and one of the most effective chemotherapeutics for the breast cancer treatment. We performed the assay for the TOP2A gene amplification and deletion on a tissue microarray (TMA) of 284 breast tumor samples from the patients treated by doxorubicin-based adjuvant chemotherapy. TOP2A gene was deleted in six patients (2.1%), whereas TOP2A gene was amplified in 20 (7.1%) of 284 tumors. Twenty-four of 26 TOP2A amplifications and deletions were associated with HER2 co-amplification. TOP2A amplification or deletion was not associated with poor clinical outcome. Nine (34.6%) of 26 patients with TOP2A amplification or deletion had recurrent disease. Thirty percent of the patients with TOP2A amplification had systemic recurrence whereas 50% of the patients with TOP2A deletion had systemic recurrence. On multivariate analysis, histologic grade and tumor size were the significant predictors for the disease-free survival and histologic grade was an only significant predictor for the overall survival. Our study indicates that response to the doxorubicin-based chemotherapy might be stratified by TOP2A amplification and deletion. However, relative low frequency of TOP2A genetic changes seems to hamper its clinical utility.

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References

  1. Early Breast Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: an overview of the randomised trials Lancet 352: 930–942 1998

    Article  Google Scholar 

  2. Zambetti M, Moliterni A, Materazzo C, Stefanelli M, Cipriani S, Valagussa P, Bonadonna G, Gianni C Long-term cardiac sequelae in operable breast cancer patients given adjuvant chemotherapy with or without doxorubicin and breast irradiation J Clin Oncol 19: 37–43 2001

    PubMed  CAS  Google Scholar 

  3. Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M, Nogaret JM Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer J Clin Oncol 19: 3103–3110 2001

    PubMed  CAS  Google Scholar 

  4. Jarvinen TAH, Tanner M, Rantanen V, Barlund M, Borg A, Grenman S, Isola J Amplification and deletion of topoisomerase IIα associate with ErbB-2 amplification and affect sensitivity to topoisomerase II inhibitor doxorubicin in breast cancer Am J Pathol 156: 839–847 2000

    PubMed  CAS  Google Scholar 

  5. Smith K, Houlbrook S, Greenall M, Carmichael J, Harris AL Topoisomerase IIα co-amplification with erbB2 in human primary breast cancer and breast cancer cell lines: relationship to m-AMSA and mitoxantrone sensitivity Oncogene 8: 933–938 1993

    PubMed  CAS  Google Scholar 

  6. Gudkov AV, Zelnick CR, Kazarov AR, Thimmapaya R, Suttle DP, Beck WT, Robinson IB Isolation of genetic suppressor elements, inducing resistance to topoisomerase II-interactive cytotoxic drugs, from human topoisomerase II cDNA Proc Natl Acad Sci USA 90: 3231–3235 1993

    Article  PubMed  CAS  Google Scholar 

  7. Withoff S, Keith WN, Knol AJ, Coutts JC, Hoare SF, Mulder NH, de Vries EGE Selection of a subpopulation with fewer DNA topoisomerase IIα gene copies in a doxorubicin-resistant cell panel Br J Cancer 74: 502–507 1996

    PubMed  CAS  Google Scholar 

  8. Zhou Z, Zwelling LA, Kawakami Y, An T, Kobayashi K, Herzog C, Kleinerman ES Adenovirus-mediated human topoisomerase IIα gene transfer increases the sensitivity of etoposide-resistant human breast cancer cells Cancer Res 59: 4618–4624 1999

    PubMed  CAS  Google Scholar 

  9. Jarvinen TA, Holli K, Kuukasjarvi T, Isola JJ Predictive value of topoisomerase IIα and other prognostic factors for epirubicin chemotherapy in advanced breast cancer Br J Cancer 77: 2267–2273 1998

    PubMed  CAS  Google Scholar 

  10. Di Leo A, Larsimont D, Gancberg D, Jarvinen T, Beauduin M, Vindevoghel A, Michel J, Focan CH, Ries F, Gobert PH, Closon-Dejardin MT, Dolci S, Rouas G, Paesmans M, Lobelle JP, Isola J, Piccart MJ HER-2 and topoisomerase IIα as predictive markers in a population of node-positive breast cancer patients randomly treated with adjuvant CMF or epirubicin plus cyclophosphamide Ann Oncol 12: 1081–1089 2001

    Article  PubMed  CAS  Google Scholar 

  11. Di Leo A, Gancberg D, Larsimont D, Tanner M, Jarvinen T, Rouas G, Dolci S, Leroy JY, Paesmans M, Isola J, Piccart MJ HER-2 amplification and topoisomerase IIα gene aberration as predictive markers in node-positive breast cancer patients randomly treated either with an anthracyclin-based therapy or with CMF Clin Cancer Res 8: 1107–1116 2002

    PubMed  CAS  Google Scholar 

  12. Coon JS, Marcus E, Gupta-Burt S, Seelig S, Jacobson K, Chen S, Renta V, Fronda G, Preisler HD Amplification and overexpression of topoisomerase IIα predict response to anthracycline-based therapy in locally advanced breast cancer Clin Cancer Res 8: 1061–1067 2002

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  14. Bofin AM, Ytterhus B, Hagmar BM TOP2A and HER-2 gene amplification in fine needle aspirates from breast carcinomas Cytopathology 14:314–319 2003

    Article  PubMed  CAS  Google Scholar 

  15. Mueller RE, Parkes RK, Andrulis IA, O’Malley FP Amplification of the TOP2A gene dies not predict high levels of topoisomerase II alpha protein in human breast tumor samples Genes Chromosome Cancer 39:288–297 2004

    Article  CAS  Google Scholar 

  16. Elston CW, Ellis IO Pathological prognostic factors in breast cancer: I. The value of histologic grade in breast cancer-experience from a large study with long-term follow-up Histopathology 19: 403–410 1991

    Article  PubMed  CAS  Google Scholar 

  17. Park K, Kim J, Lim S, Han S, Lee JY Comparing fluorescence in situ hybridization and chromogenic in situ hybridization methods to determine the HER2/neu status in primary breast carcinoma using tissue microarray Mod Pathol 16: 937–943 2003

    Article  PubMed  Google Scholar 

  18. Jarvinen TA, Tanner M, Barlund M, Borg A, Isola J Characterization of topoisomerase IIα gene amplification and deletion in breast cancer Genes Chromosome Cancer 26: 142–150 1999

    Article  CAS  Google Scholar 

  19. Luoh SW Amplification and expression of genes from the 17q11-q12 amplicon in breast cancer cells Cancer Genet Cytogenet 136:43–47 2002

    Article  PubMed  CAS  Google Scholar 

  20. Hyman E, Kauraniemi P, Hautaniemi S, Wolf M, Mousses S, Rozenblum E, Ringner M, Sauter G, Monni O, Elkahloun A, Kallioniemi OP, Kallioniemi A Impact of DNA amplification on gene expression patterns in breast cancer Cancer Res 62:6240–6245 2002

    PubMed  CAS  Google Scholar 

  21. Clark J, Edwards S, John M, Flohr P, Gordon T, Maillard K, Giddings I, Brown C, Bagherzadeh A, Campbell C, Shipley J, Wooster R, Cooper CS Identification of amplified and expressed genes in breast cancer by comparative hybridization onto microarrays of randomly selected cDNA clones Genes Chromosome Cancer 34:104–114 2002

    Article  CAS  Google Scholar 

  22. Kauraniemi P, Kuukasjarvi T, Sauter G, Kallioniemi A Amplification of a 280-kilobase core region at the ERBB2 locus leads to activation of two hypothetical proteins in breast cancer Am J Pathol 163:1979–1984 2003

    PubMed  CAS  Google Scholar 

  23. Jacobson KK, Morrison LE, Henderson BT, Blondin BA, Wilber KA, Legator MS, O’Hare A, Van Stedum SC, Proffitt JH, Seelig SA, Coon JS Gene copy mapping of the ERBB2/TOP2A region in breast cancer Genes Chromosome Cancer 40:19–31 2004

    Article  CAS  Google Scholar 

  24. Knoop AS, Knudsen H, Balslev E, Rasmussen BB, Overgaard J, Nielsen KV, Schonau A, Gunnarsdottir K, Olsen KE, Mouridsen H, Ejlertsen B 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 23:7483–7490 2005

    Article  PubMed  CAS  Google Scholar 

  25. Cardoso F, Durbecq V, Larsimont D, Paesmans M, Leroy JY, Rous G, Sotiriou C, Renard N, Richard V, Piccart MJ, Di Leo A Correlation between complete response to anthracycline-based chemotherapy and topoisomerase II-alpha gene amplification and protein overexpression in locally advanced/metastatic breast cancer Int J Oncol 24: 201–209 2004

    PubMed  CAS  Google Scholar 

  26. Schindlbeck C, Janni W, Shabani N, Kornmeier A, Rack B, Rjosk D, Gerber B, Braun S, Sommer H, Friese K Isolated tumor cells in the bone marrow (ITC-BM) of breast cancer patients before and after anthracycline based therapy: influenced by the HER2- and topoisomerase IIα-status of the primary tumor? J Cancer Res Clin Oncol 131:539–546 2005

    Article  PubMed  CAS  Google Scholar 

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Acknowledgement

This work was supported by the 2003 Inje University research grant for Sehwan Han.

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Authors and Affiliations

  1. Department of Pathology, Inje University Sanggye Paik Hospital, 761-1, Sanggye-dong, Nowon-gu, 139-707, Seoul, South Korea

    Kyeongmee Park, Huyn-jung Kim & Jungyeon Kim

  2. Department of Surgery, Inje University Sanggye Paik Hospital, 761-1, Sanggye-dong, Nowon-gu, 139-707, Seoul, South Korea

    Sehwan Han & Geum-Hee Gwak

  3. Department of Pathology, Samsung Medical Center, Sungkyunkwan University, IIwon-dong, Kangnam-gu, 135-710, Seoul, South Korea

    Kyoung-Mee Kim

  4. Department of Surgery, Inje University Sanggye Paik Hospital, 761-1, Sanggye-dong, Nowon-gu, 139-707, Seoul, South Korea

    Sehwan Han

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  1. Kyeongmee Park
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  2. Sehwan Han
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  3. Geum-Hee Gwak
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  4. Huyn-jung Kim
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Correspondence to Sehwan Han.

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

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  • DOI: https://doi.org/10.1007/s10549-006-9170-7

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