7153

TOP2A

topoisomerase (DNA) II alpha 170kDa;TOP2A;topoisomerase (DNA) II alpha 170kDa

DNA gyrase|DNA topoisomerase (ATP-hydrolyzing)|DNA topoisomerase 2-alpha|DNA topoisomerase II, 170 kD|DNA topoisomerase II, alpha isozyme

17q21-q22

protein-coding

The aim of this study was to determine the relationship between amplification of HER2 (Human epidermal growth factor receptor 2) and Topo2a (topoisomerase 2a) and their influence on prognosis in metastatic breast cancer (MBC) patients. Amplification of both HER2 and Topo2a genes was determined by chromogenic in situ hybridization (CISH) in primary tumor tissue of 71 MBC patients. Starting point for follow-up was the time of diagnosis of metastatic disease. Although there was significant correlation between HER2 amplification and Topo2a alterations, Topo2a amplification was not strictly related to HER2 amplification. Follow-up of patients showed that there was no difference in MBC survival between HER2-nonamplified and HER2-amplified patients for subgroup as whole, but there was significant difference in MBC survival between patients with and without Topo2a amplification. HER2 amplification showed prognostic value in subgroups of patients, as well as Topo2a. Combination of these two genes with different status (nonamplified, amplified, coamplified) indicated that they might have additive effect. Also, it has been shown that Topo2a-amplified cases have poorer survival than Topo2a-nonamplified, when treated with CMF therapy. Topo2a amplification seems to be more promising biomarker of MBC survival, than HER2, and potential marker of resistance to CMF therapy.

At recurrence of breast cancer, the therapeutic target is the metastases. However, it is current practice to base the choice of systemic treatment on the biomarker profile of the primary tumor. In the present study, confirmatory biopsies were obtained from suspected metastatic lesions and compared with the primary tumors with respect to ER, HER2, and TOP2A. In the prospective tissue-collection study, 81 patients had biopsy from a suspected relapse. Additional archived paired material was included, leaving a total of 119 patients with paired primary tumor, synchronous axillary nodes (available in 52 patients) and asyncronous metastases available for analysis. ER, HER2, and TOP2A expression of primary tumors, axillary nodes and metastases were re-analysed and determined centrally by immunohistochemistry, chromogenic in situ hybridization, and fluorescence in situ hybridization. Of the 81 patients with a biopsy from a suspected relapse, 65 (80%) were diagnosed with recurrent breast carcinoma, 3 (4%) were diagnosed with other malignancies, 6 (7%) had benign conditions, and in 7 (9%) patients the biopsy was non-representative. Discordance in ER, HER2, and TOP2A (aberration vs. normal) status between primary tumor and corresponding asynchronous metastasis was 12% (14/118), 9% (10/114), and 23% (17/75), respectively. There were no significant associations with biomarker discordance and prior adjuvant therapy, or location of biopsy. expression of ER, HER2, and TOP2A displayed discordance with a sufficient frequency to emphasize the role of confirmatory biopsies from metastatic lesions in future management of recurrent breast cancer.

OBJECTIVE: The aim of this study was to assess the TOP2A RNA expression and the relationship of TOP2A protein expression with metastasis-free interval in breast cancer patients. METHODS: TOP2A expression was analyzed prior to surgery in 86 patients. The level of TOP2A gene amplification was analyzed by fluorescence in situ hybridization (FISH), its RNA expression level with RT-PCR, and their correlation with TOP2A protein expression was assessed by immunohistochemistry (IHC). The correlation between RNA expression level and metastasis-free interval in breast cancer patients was also analyzed. RESULTS: Aberrations (amplification or deletion) of TOP2A copy number was observed in 25.6% (22/86) of the cases. TOP2A protein expression was detected in 66.3% (57/86) of the samples. There was a significant correlation between the TOP2A RNA expression and protein expression (P < 0.001). TOP2A gene expression was significantly associated with the metastasis-free interval in the breast cancer patients (P = 0.001). There was no significant correlation between TOP2A gene amplification and TOP2A protein expression (P = 0.211). CONCLUSIONS: TOP2A RNA level is an objective and reliable prognostic indicator in breast cancer.

OBJECTIVE: To detect the correlation between the expression of topoisomerase 2 alpha (TOP2A) and the biological behaviors of human colorectal carcinoma. METHODS: Immunohistochemistry and real-time RT-PCR were used to detect the expression of TOP2A in colorectal carcinomas and normal mucosa. RESULTS: The protein and mRNA expressions of TOP2A in the metastatic lymph nodes were significantly higher than those in matched primary lesions and normal tissues (P<0.05). No significant difference was found in TOP2A expressions between normal mucosa and colorectal carcinomas. The protein and mRNA expressions of TOP2A were significantly correlated to the lymph node metastasis and invasion depth (P<0.05), but not to the differentiation of the tumor (P>0.05). CONCLUSION: TOP2A plays an important role in the invasion and metastasis of the colorectal carcinomas, and may serve as a valuable indicator for the diagnosis, treatment and the prognostic evaluation of the malignancy.

OBJECTIVE: The purpose of this study was to investigate the markers which can be used in auxiliary diagnosis of gastric adenocarcinoma (GAC), and their correlation with their clinicopathological features. METHODS: 122 surgical specimens including 99 gastric adenocarcinoma (GAC), 18 adjacent mucosa and 5 distal normal mucosa were collected, and analyzed by in situ hybridization (FISH). The centromere probe cen17, specific for chromosome 17, which was reported to be frequently amplified in GAC, was selected for the FISH analysis. The clinicopathological features of the 99 GAC cases were reviewed, and the level of TP53 and TOPIIalpha gene expression, located in chromosome 17, was detected using tissue micro-array (TMA), compared with that of corresponding adjacent normal mucosa. Data were analyzed with SPSS 11.5 for Windows. RESULTS: The statistical results of FISH and TMA showed that 58.6% of cen17 in tumor tissues were aneuploid, and 45.5% of TP53 and 84.7% of TOPIIalpha were over-expressed in GAC samples, significantly higher than those in non-tumor gastric mucosa (0, 12.1% and 14.1%, respectively) (P = 0.000). 58 GAC tissues were aneuploid of cen17, including 26 cases TP53-positive and 49 cases TOPIIalpha-positive. The expression of TP53 in non-tumor gastric mucosa with dysplasia was significantly higher than that in the mucosa without dysplasia (P = 0.009). Aneuploidy of cen17 was more frequent in grade 1 or 2 than in grade 3 GAC (P < 0.05). Higher frequency of aneuploidy of cen17 was also observed in the gastric cardia than in pylorus (P < 0.05), while no correlation was found between aneuploidy of cen17 and age, sex of patients, lymph node metastasis, and clinical stage of tumors. Over-expression of TP53 protein was associated with the size of tumors (P < 0.05). In addition, a negative correlation was observed between over-expression of TOPIIalpha and lymph node metastasis (LNM) as well as TNM classification (P < 0.05). CONCLUSION: Detection of aneuploidy of cen17 as well as over-expression of TP53 and TOPIIalpha may be helpful in the diagnosis and prognostic prediction of gastric adenocarcinoma.

The aim of this study was to investigate the mRNA expression levels of multidrug resistance-associated proteins in chemo-naive metastatic lung cancer cells and to determine the correlation with response to chemotherapy and overall survival. metastatic cells were obtained by transbronchial fine needle aspiration biopsy of enlarged mediastinal lymph nodes in 14 patients with small cell lung cancer (SCLC) and 7 patients with non-small cell lung cancer (NSCLC). After cytological confirmation of lung cancer type, total RNA was extracted from biopsy samples and reverse transcribed to cDNA, and real-time PCR for the genes of interest [P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), breast cancer resistance protein (BCRP), lung resistance protein (LRP) and topoisomerase IIalpha (TOPIIalpha)], was performed. We observed significantly decreased expression of BCRP and significantly increased expression of TOPIIalpha in metastatic SCLC cells compared to NSCLC. Furthermore, in SCLC high topoisomerase IIalpha and low BCRP expression levels positively correlated with longer overall survival. Our results showed higher expression levels of BCRP as well as lower levels of topoisomerase IIalpha in chemo-naive metastatic cells in NSCLC than in SCLC. These results correlate with previous observations that metastatic SCLC cells at the beginning of chemotherapy are potentially more sensitive to chemotherapeutic agents while in metastatic NSCLC cells resistance is usually inherent. We also showed that altered levels of topoisomerase IIalpha and BCRP in SCLC are important factors that contribute to resistance to chemotherapeutics that interfere with the enzyme and/or DNA and are highly associated with overall survival.