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

• 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 [9].
• Sequence identity comparisons between eukaryotic DNA topoisomerase II and bacterial gyrase (bacterial DNA topoisomerase II) indicate that the position of the common mutation observed in mAMSA-resistant human TOP2 corresponds to that of the point mutation nal-31 in the Escherichia coli gyrase B gene, which confers resistance to nalidixic acid [10].

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

• TOP2A is amplified or deleted together with amplification of the closely located ERBB2/HER-2/neu oncogene in breast cancer [11].

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

• TOP2A is frequently coamplified with c-erb-B2 and consequently might be a prognostic and/or predictive factor for breast cancer patients when anthracycline-based chemotherapy is a consideration [4].
• Further examination by fluorescence in situ hybridization revealed amplification of TOP2A in 13 of the 38 cases [27].
• Of these 9 cases, 3 displayed coamplification of TOP2A and HER2, and only 1 of the 3 cases revealed a high expression of topoIIalpha in Western blot [27].
• Although patients having gastric adenocarcinoma with TOP2A amplification could be considered suitable for clinical trials, information involving anthracycline therapy is not firmly understood in regards to the status of TOP2A amplification or protein overexpression [27].
• Simultaneous Amplification of HER-2 (ERBB2) and Topoisomerase IIalpha (TOP2A) Genes - Molecular Basis for Combination Chemotherapy in Cancer [28].

References