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Gene Review

TOP2A  -  topoisomerase (DNA) II alpha 170kDa

Homo sapiens

Synonyms: DNA topoisomerase 2-alpha, DNA topoisomerase II, alpha isozyme, TOP2, TP2A
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Disease relevance of TOP2A

  • CONCLUSION: TOP2A amplification-and possibly deletion-seems to be predictive markers for the effect of adjuvant epirubicin containing therapy in primary breast cancer, but a final conclusion has to await a confirmative study or a meta-analysis [1].
  • In our study, we characterized the amplification (52 cases) and expression (29 cases) levels of ERBB2, TOP2A and DARPP32 in gastric cancer samples [2].
  • The modulation of two representative genes, CDKN1A and TOP2A, was validated by Northern analyses on a panel of seven ovarian carcinoma xenograft models undergoing treatment with paclitaxel [3].
  • A total of 20% to 35% of breast carcinomas show amplification of the erb-B2 gene, some of which also have coamplification of the TOP2A gene [4].
  • Previous studies have suggested that amplification of genes, notably the TOP2A gene, on chromosome arm 17q may be important for the development of malignant peripheral nerve sheath tumour (MPNST) [5].

High impact information on TOP2A

  • The formation of these HMW DNA fragments is reversible and shown to be mediated by DNA topoisomerase II (TOP2) [6].
  • Our results thus demonstrate a potential role of TOP2 in oxidative damage of DNA and apoptotic cell death [6].
  • METHODS: We characterized a rearrangement of the topoisomerase II p170 gene (also known as TOP2) in a relatively chemoresistant SCLC cell line, NCI-H69, and compared topoisomerase II expression and activity in this line with those in the chemosensitive NCI-H187 cell line [7].
  • Tyrosyl-DNA phosphodiesterase (Tdp1) participates in the repair of Top2-mediated DNA damage [8].
  • We found that deletion of the TDP1 gene in yeast confers hypersensitivity to Top2 targeting agents [8].

Chemical compound and disease context of TOP2A


Biological context of TOP2A

  • This is in contrast to patients with a normal TOP2A genotype for whom similar outcome was observed in both treatment arms (RFS: HR, 0.90; 95% CI, 0.70 to 1.17; OS: HR, 0.88; 95% CI, 0.66 to 1.17) [1].
  • These results indicate that amplification of the ERBB2 oncogene is followed by complex secondary genetic aberrations, which lead to amplification or deletion of the TOP2A gene in a majority of tumors [11].
  • Topoisomerase IIalpha (TOP2A) is a key enzyme in DNA replication and a molecular target for many important anticancer drugs [11].
  • To study the amplification and expression of TOP2A and HER-2 and associations with tumor phenotype and clinical outcome in bladder cancer, a tissue microarray containing 2,317 bladder tumor samples was analyzed by FISH and immunohistochemistry [12].
  • Mean copy numbers of TOP2A (2.4 +/- 0.6 for TOP2A vs. 4.9 +/- 1.1 for chromosome 17 centromere) suggest that the deletion of TOP2A occurs before polyploidization of the genome [11].

Anatomical context of TOP2A

  • The deletion of TOP2A (seen in the MDA-361 cell line and in 31 primary tumors) was interstitial, spanning less than two megabases of DNA [11].
  • Normal pancreatic ductal epithelium, proposed to give rise to pancreatic adenocarcinoma, did not demonstrate detectable TOP2A expression [13].
  • This study was designed to correlate the presence and activity of two proteins at the centromeric heterochromatin, topoisomerase II alpha (TOP2A) and histone H3, with the processes of chromosome condensation and individualization of chiasmate bivalents in murine spermatocytes [14].
  • SK-Br3 cells cultured in the presence of topoisomerase IIalpha (TOP2A) inhibitors doxorubicin and etopoxide (VP-16) demonstrated a 2- to 3-fold increase in FAS promoter activity when compared with control cells growing in drug-free culture conditions [15].
  • OBJECTIVE: The aim of this study was to evaluate the expression of topoisomerase IIalpha (TOP2A) in epithelial and stromal cells of ovarian cancer [16].

Associations of TOP2A with chemical compounds

  • Within the doxorubicin-resistant group, distinct features of candidate genes overexpressions including ABC transporting proteins, solute carriers and TOP2A were suggested [17].
  • The presence of TOP2A amplification in advanced cancer was associated with androgen resistance and decreased survival by multivariate analysis [18].
  • Locus specific ERBB2, TOP2A genes and chromosome 17 centromeres (CEP17) probes were hybridized to 72 formalin-fixed paraffin-embedded (FFPE) tissue samples from patients with non-metastatic breast carcinoma (M0) [19].
  • Because the orientations of the intercalated hydrocarbon are known from NMR solution structures of duplex oligonucleotides containing these dA adducts, a detailed analysis of the relationship between the position of intercalation and trapping of Top2 is possible [20].
  • A compound with a novel structure, NSC 665517, was tested in the National Cancer Institute Preclinical Drug Discovery Screen. With the COMPARE algorithm, the pattern of differential cytotoxicity for NSC 665517 most closely resembled those of known topoisomerase II (top2) inhibitors [21].

Physical interactions of TOP2A

  • Of note, when the expression levels of TOP2A protein were analyzed following exposure of SK-Br3 cells to increasing concentrations of the novel slow-binding FAS inhibitor C75, a dose-dependent reduction in TOP2A expression was observed [15].

Enzymatic interactions of TOP2A


Regulatory relationships of TOP2A

  • Binding of p53 has been shown to inhibit transcription of TOP2 alpha [22].
  • Bulky substitution at position 11 determined different patterns of top2 cleavage sites and suppressed the action on tubulin [23].

Other interactions of TOP2A

  • No TOP2A gene aberrations were identified in 65 primary tumors without ERBB2 amplification [11].
  • TOP2A is approx. 30kb whereas TOP2B is at least 49kb [24].
  • However, the expression levels were independent, showing overexpression of DARPP32 (48%), TOP2A (17%) and ERBB2 (3%) studied by quantitative real-time PCR [2].
  • These genes include all 9 genes that are fully or partially located inside the CTD-2019C10 clone as well as 2 additional adjacent genes (NEUROD and TOP2A) [25].
  • By fluorescence in situ hybridization (FISH), the insertion was shown to be an amplification of part of 17q, involving ERBB2, RARA, and TOP2A genes [26].

Analytical, diagnostic and therapeutic context of TOP2A


  1. 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. Knoop, A.S., Knudsen, H., Balslev, E., Rasmussen, B.B., Overgaard, J., Nielsen, K.V., Schonau, A., Gunnarsdóttir, K., Olsen, K.E., Mouridsen, H., Ejlertsen, B. J. Clin. Oncol. (2005) [Pubmed]
  2. Coamplified and overexpressed genes at ERBB2 locus in gastric cancer. Varis, A., Zaika, A., Puolakkainen, P., Nagy, B., Madrigal, I., Kokkola, A., Väyrynen, A., Kärkkäinen, P., Moskaluk, C., El-Rifai, W., Knuutila, S. Int. J. Cancer (2004) [Pubmed]
  3. Gene expression correlating with response to paclitaxel in ovarian carcinoma xenografts. Bani, M.R., Nicoletti, M.I., Alkharouf, N.W., Ghilardi, C., Petersen, D., Erba, E., Sausville, E.A., Liu, E.T., Giavazzi, R. Mol. Cancer Ther. (2004) [Pubmed]
  4. Copy number analysis of c-erb-B2 (HER-2/neu) and topoisomerase IIalpha genes in breast carcinoma by quantitative real-time polymerase chain reaction using hybridization probes and fluorescence in situ hybridization. Murthy, S.K., Magliocco, A.M., Demetrick, D.J. Arch. Pathol. Lab. Med. (2005) [Pubmed]
  5. Identification of a novel amplicon at distal 17q containing the BIRC5/SURVIVIN gene in malignant peripheral nerve sheath tumours. Storlazzi, C.T., Brekke, H.R., Mandahl, N., Brosjö, O., Smeland, S., Lothe, R.A., Mertens, F. J. Pathol. (2006) [Pubmed]
  6. Activation of topoisomerase II-mediated excision of chromosomal DNA loops during oxidative stress. Li, T.K., Chen, A.Y., Yu, C., Mao, Y., Wang, H., Liu, L.F. Genes Dev. (1999) [Pubmed]
  7. Characterization of a topoisomerase II gene rearrangement in a human small-cell lung cancer cell line. Binaschi, M., Giaccone, G., Gazdar, A.F., De Isabella, P., Ricotti, G.C., Capranico, G., Zunino, F. J. Natl. Cancer Inst. (1992) [Pubmed]
  8. Tyrosyl-DNA phosphodiesterase (Tdp1) participates in the repair of Top2-mediated DNA damage. Nitiss, K.C., Malik, M., He, X., White, S.W., Nitiss, J.L. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  9. Topoisomerase II-alpha gene deletion is not frequent as its amplification in breast cancer. Park, K., Han, S., Gwak, G.H., Kim, H.J., Kim, J., Kim, K.M. Breast Cancer Res. Treat. (2006) [Pubmed]
  10. Two independent amsacrine-resistant human myeloid leukemia cell lines share an identical point mutation in the 170 kDa form of human topoisomerase II. Lee, M.S., Wang, J.C., Beran, M. J. Mol. Biol. (1992) [Pubmed]
  11. Characterization of topoisomerase II alpha gene amplification and deletion in breast cancer. Järvinen, T.A., Tanner, M., Bärlund, M., Borg, A., Isola, J. Genes Chromosomes Cancer (1999) [Pubmed]
  12. HER-2 and TOP2A coamplification in urinary bladder cancer. Simon, R., Atefy, R., Wagner, U., Forster, T., Fijan, A., Bruderer, J., Wilber, K., Mihatsch, M.J., Gasser, T., Sauter, G. Int. J. Cancer (2003) [Pubmed]
  13. A subset of pancreatic adenocarcinomas demonstrates coamplification of topoisomerase IIalpha and HER2/neu: use of immunolabeling and multicolor FISH for potential patient screening andtreatment. Hansel, D.E., Ashfaq, R., Rahman, A., Wanzer, D., Yeo, C.J., Wilentz, R.E., Maitra, A. Am. J. Clin. Pathol. (2005) [Pubmed]
  14. Meiotic events at the centromeric heterochromatin: histone H3 phosphorylation, topoisomerase II alpha localization and chromosome condensation. Cobb, J., Miyaike, M., Kikuchi, A., Handel, M.A. Chromosoma (1999) [Pubmed]
  15. DNA topoisomerase IIalpha (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: In vitro evidence for a 'functional amplicon' involving FAS, Her-2/neu and TOP2A genes. Menendez, J.A., Vellon, L., Lupu, R. Int. J. Mol. Med. (2006) [Pubmed]
  16. Altered Expression Pattern of Topoisomerase IIalpha in Ovarian Tumor Epithelial and Stromal Cells after Platinum-Based Chemotherapy. Chekerov, R., Klaman, I., Zafrakas, M., Könsgen, D., Mustea, A., Petschke, B., Lichtenegger, W., Sehouli, J., Dahl, E. Neoplasia (2006) [Pubmed]
  17. Karyotypic imbalances and differential gene expressions in the acquired doxorubicin resistance of hepatocellular carcinoma cells. Pang, E., Hu, Y., Chan, K.Y., Lai, P.B., Squire, J.A., Macgregor, P.F., Beheshti, B., Albert, M., Leung, T.W., Wong, N. Lab. Invest. (2005) [Pubmed]
  18. Low-level TOP2A amplification in prostate cancer is associated with HER2 duplication, androgen resistance, and decreased survival. Murphy, A.J., Hughes, C.A., Barrett, C., Magee, H., Loftus, B., O'Leary, J.J., Sheils, O. Cancer Res. (2007) [Pubmed]
  19. Analysis of ERBB2 and TOP2A gene status using fluorescence in situ hybridization versus immunohistochemistry in localized breast cancer. Bouchalov??, K., Trojanec, R., Kol??r, Z., Cwiertka, K., Cern??kov??, I., Mih??l, V., Hajd??ch, M. Neoplasma (2006) [Pubmed]
  20. Position-specific trapping of topoisomerase II by benzo[a]pyrene diol epoxide adducts: implications for interactions with intercalating anticancer agents. Khan, Q.A., Kohlhagen, G., Marshall, R., Austin, C.A., Kalena, G.P., Kroth, H., Sayer, J.M., Jerina, D.M., Pommier, Y. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  21. Eukaryotic DNA topoisomerases mediated DNA cleavage induced by a new inhibitor: NSC 665517. Gupta, M., Abdel-Megeed, M., Hoki, Y., Kohlhagen, G., Paull, K., Pommier, Y. Mol. Pharmacol. (1995) [Pubmed]
  22. Differential effect of camptothecin treatment on topoisomerase II alpha expression in ML-1 and HL-60 leukemia cell lines. Nair, J., Traganos, F., Tse-Dinh, Y.C. Anticancer Res. (2000) [Pubmed]
  23. Azatoxin derivatives with potent and selective action on topoisomerase II. Leteurtre, F., Sackett, D.L., Madalengoitia, J., Kohlhagen, G., MacDonald, T., Hamel, E., Paull, K.D., Pommier, Y. Biochem. Pharmacol. (1995) [Pubmed]
  24. Structural organization of the human TOP2A and TOP2B genes. Lang, A.J., Mirski, S.E., Cummings, H.J., Yu, Q., Gerlach, J.H., Cole, S.P. Gene (1998) [Pubmed]
  25. Molecular dissection of 17q12 amplicon in upper gastrointestinal adenocarcinomas. Maqani, N., Belkhiri, A., Moskaluk, C., Knuutila, S., Dar, A.A., El-Rifai, W. Mol. Cancer Res. (2006) [Pubmed]
  26. Amplification of ERBB2, RARA, and TOP2A genes in a myelodysplastic syndrome transforming to acute myeloid leukemia. Martín-Subero, J.I., Harder, L., Gesk, S., Schoch, R., Novo, F.J., Grote, W., Calasanz, M.J., Schlegelberger, B., Siebert, R. Cancer Genet. Cytogenet. (2001) [Pubmed]
  27. Topoisomerase IIalpha gene amplification in gastric carcinomas: correlation with the HER2 gene. An immunohistochemical, immunoblotting, and multicolor fluorescence in situ hybridization study. Kanta, S.Y., Yamane, T., Dobashi, Y., Mitsui, F., Kono, K., Ooi, A. Hum. Pathol. (2006) [Pubmed]
  28. Simultaneous Amplification of HER-2 (ERBB2) and Topoisomerase IIalpha (TOP2A) Genes - Molecular Basis for Combination Chemotherapy in Cancer. J??rvinen, T.A., Liu, E.T. Current cancer drug targets (2006) [Pubmed]
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