Multiplication of Chromosome 17 Centromere Is Associated with Prognosis in Patients with Invasive Breast Cancers Exhibiting Normal HER2 and TOP2A Status / 한국유방암학회지

PURPOSE: This study aimed to investigate the clinical significance of chromosome 17 centromere (CEP17) multiplication (increased copy number of CEP17) related to human epidermal growth factor receptor 2 (HER2) and topoisomerase II alpha (TOP2A) status in patients with invasive breast cancer. METHODS: We constructed tissue microarrays using 594 invasive breast cancer samples and performed single-color silver-enhanced in situ hybridization (SISH) assay for HER2, TOP2A, and CEP17 to assess for copy number aberrations. The association of CEP17 multiplication with patient survival was analyzed according to HER2 and TOP2A status. RESULTS: Among 567 informative cases, HER2 amplification was noted in 22.8%, TOP2A amplification in 8.3% and TOP2A deletion in 11.1%. CEP17 multiplication was identified in 33.2% and was significantly associated with worse overall survival (OS) (p=0.02) and disease-free survival (DFS) (p=0.02). CEP17 multiplication correlated with patient survival in patients with normal TOP2A or non-amplified HER2 status, but the prognostic significance was lost in those with altered TOP2A or amplified HER2. On multivariate analyses, CEP17 multiplication was an independent prognostic factor for poorer OS (p=0.02) and DFS (p=0.01) in patients with normal TOP2A and non-amplified HER2. CONCLUSION: CEP17 multiplication was identified as a promising prognostic marker in patients with invasive breast cancer exhibiting either non-amplified HER2 or normal TOP2A status.

Multiplication of Chromosome 17 Centromere Is Associated with Prognosis in Patients with Invasive Breast Cancers Exhibiting Normal HER2 and TOP2A Status / 한국유방암학회지

PURPOSE: This study aimed to investigate the clinical significance of chromosome 17 centromere (CEP17) multiplication (increased copy number of CEP17) related to human epidermal growth factor receptor 2 (HER2) and topoisomerase II alpha (TOP2A) status in patients with invasive breast cancer. METHODS: We constructed tissue microarrays using 594 invasive breast cancer samples and performed single-color silver-enhanced in situ hybridization (SISH) assay for HER2, TOP2A, and CEP17 to assess for copy number aberrations. The association of CEP17 multiplication with patient survival was analyzed according to HER2 and TOP2A status. RESULTS: Among 567 informative cases, HER2 amplification was noted in 22.8%, TOP2A amplification in 8.3% and TOP2A deletion in 11.1%. CEP17 multiplication was identified in 33.2% and was significantly associated with worse overall survival (OS) (p=0.02) and disease-free survival (DFS) (p=0.02). CEP17 multiplication correlated with patient survival in patients with normal TOP2A or non-amplified HER2 status, but the prognostic significance was lost in those with altered TOP2A or amplified HER2. On multivariate analyses, CEP17 multiplication was an independent prognostic factor for poorer OS (p=0.02) and DFS (p=0.01) in patients with normal TOP2A and non-amplified HER2. CONCLUSION: CEP17 multiplication was identified as a promising prognostic marker in patients with invasive breast cancer exhibiting either non-amplified HER2 or normal TOP2A status.

Immunohistochemical Studies of Fascin, MMP-9 Overexpression, and Proliferating Index as Prognostic Factors in Cases of a Colon Adenocarcinoma

PURPOSE: The malignant conversion of epithelial cells involves alterations in the expression and the function of cell-matrix and cell-cell adhesive systems that enable a switch to a migratory phenotype in tumor invasion and metastasis. Here, the author studies the prevalence and the potential clinical significance of fascin and Matrix metalloproteinase-9 (MMP-9) expression in relation to the progression of colon adenocarcinoma and of tumor cell proliferation as measured by using the topoisomerase II-alpha (Topo II-alpha) index. METHODS: Relatively well-preserved paraffin-embedded tissues of 120 cases of colon adenocarcinomas were immunohistochemically stained for fascin, MMP-9, and Topo II-alpha expression. A reaction was determined as being positive when more than 10% of the cells were positive for fascin, and/or MMP-9. The Topo II-alpha index is defined as the positive number of tumor cells divided by the total number of tumor cells counted times 100. At least 1,000 cells were counted for this analysis. A chi-square test, by using Epi info 2000, for Fascin and/or MMP-9 and a two-sided test for the Topo II-alpha index were employed with a significance of P65 yr, P=0.028), tumor grading (P=0.009), and lymph node metastases (P=0.005). However, MMP-9 immunoreactivity was not statistically associated with age, gender, tumor stage, or lymph node metastases. Fascin expression was statistically associated with MMP-9 expression, especially for left colon adenocarcinomas (P=0.0032). Although the topo II-alpha proliferating index was associated with lymph node metastasis (P<0.01), this result was not statistically associated with Fascin or MMP-9 expression. CONCLUSION: Fascin expression may be closely linked with tumor grading and lymph node metastasis of more aggressive colon adenocarcinomas and partly associated with MMP-9 expression in tumor invasion. However, further studies of fascin expression as an independent prognostic factor are required for the determination of significant relationships with other clinicopathologic indices.

Amplification of the HER-2/neu Oncogene and Topoisomerase II-alpha by Chromogenic in Situ Hybridization in Breast Cancer

PURPOSE: HER-2/neu is the most frequently amplified oncogene in breast cancer. Topoisomerase II-alpha is a key enzyme in DNA replication and it is a molecular target for many anti-cancer drugs that are called topo II inhibitors; in addition, it is a new marker of proliferation. Because of the physical proximity of the ER-2/neu and topoisomerase II-alpha genes, co-amplification of the HER-2/neu and topoisomerase II-alpha may be important determinates of the response to chemotherapy for advanced breast cancer patients. METHODS: We studied the correlation of gene amplification of HER-2/neu and topoisomerase II-alpha by chromogenic in situ hybridization (CISH) in 43 infiltrating duct carcinomas of the breast. The over-expression of HER-2/neu protein and the staining index for the proliferation marker of topoisomerase II-alpha were examined immunohistochemically. The correlations between the status of HER-2/neu and topoisomerase II-alpha and the other clinicopathologic variables such as tumor size, lymph node metastasis, TNM stage, histologic grade, nuclear grade, and the estrogen receptor and progesteron receptor were investigated. RESULTS: Of the 43 infiltrating ductal carcinomas, the amplifications of HER-2/neu and topoisomerase II-alpha by CISH were observed in 8 cases (18.6%) and 14 cases (32.6%), respectively. Amplification of HER-2/neu showed the statistically significant correlations with tumor size, histologic grade and the topoisomerase II-alpha staining index. Amplification of topoisomerase II-alpha showed statistically significant correlations with axillary lymph node metastasis, the stage, the nuclear grade and the estrogen receptor status. CONCLUSION: These data suggest that amplification of HER-2/neu oncogene and topoisomerase II-alpha by CISH may be valuable for determining the response to chemotherapy, and detection of HER-2/neu and topoisomerase II-alpha in tumor sections may have prognostic value in human breast cancer.

p53, Heat Shock Protein 70 and Topoisomerase II Expression in Gallbladder Carcinoma

BACKGROUND: The present study was designed to investigate the expression of p53, Heat Shock Protein 70 (HSP70), and Topoisomerase (Topo) II alpha in the preneoplastic lesions and carcinomas of the gallbladder (GB) and to assess the correlation between the expression of these proteins and the clinicopathologic parameters by performing immunohistochemistry. METHODS: The immunohistochemical expressions of p53, HSP70 and Topo II alpha were evaluated in 38 gallbladder carcinomas and 3 adenomas. Fifteen CIS(s) and 8 dysplasias that were located adjacent to invasive carcinomas were also studied. RESULTS: A p53 expression was identified in 22 (57.9%) of the 38 GB carcinomas, in 9 (64.3%) of 14 CISs, and in none of the 8 dysplasias and 3 adenomas. A HSP70 expression was found in 11 (29%) of the 38 carcinomas, in 11 (78.6%) of 14 CIS(s), and in 4 (57.2%) of 7 dysplasias. A Topo II alpha expression was present in 36 (94.7%) of the 38 carcinomas, in 13 (92.9%) of 14 CIS(s), in 7 (100%) of 7 dysplasias and in 3 (100%) of 3 adenomas. p53 overexpression was related to the T stage of the primary tumor, while HSP70 and Topo II alpha were not related to any of the clinicopathologic parameters. CONCLUSION: p53 may be involved in GB carcinogenesis and in the progression of cancer. p53 may be also helpful for making the differential diagnosis between dysplasia and CIS. A further large study is needed to better elucidate the roles of HSP70 and Topo II alpha in GB carcinogenesis.

Proliferative Markers of Breast Cancer / 한국유방암학회지

PURPOSE: The mitotic index (MI) and Ki-67 labeling index have been used as cell proliferative markers in the various tumors. Topoisomerase II alpha (Topo II alpha) is also expressed in proliferating cells. The aim of this study was to evaluate the correlations between the MI, Ki-67, and Topo II alpha expression as proliferative markers of breast cancer. METHODS: The cell proliferative activity of 181 breast cancers was measured using MI, Ki-67 labeling index and Topo II alpha expression. The correlation between the measured markers was also analyzed. RESULTS: The MI, Ki-67, and Topo II alpha were significantly correlated with each other(p < 0.000). The MI and Ki-67 labeling index were associated with high histological grade, and absence of hormone receptor (p < 0.000). Topo II alpha expression was correlated with high histological grade (p < 0.000), absence of hormone receptor and HER-2/neu overexpression (p < 0.043). The MI, Ki-67, and Topo II alpha were not associated with any other clinical variables, such as age, tumor size, and lymph node status. CONCLUSION: The three proliferative indices were significantly associated with aggressive features of breast cancer, and significantly correlated with each other.

Immunohistochemical Study of Metallothionein Expression in Colonic Adenocarcinoma: Correlation with p53, Topoisomerase II-alpha Expression and Apoptosis

PURPOSE: Although immunohistochemically detectable metallothionein (MT) overexpression has been described in proliferation epithelial tumor cells, the clinical significance of the expression remains to be elucidated. Therefore, the present article is focused on evaluating the possible significance of MT expression in colonic adenocarcinoma and its relationship with p53 overexpression, Topoisomerase II-alpha as new cell proliferating marker and apoptosis. METHODS: The following formalin-fixed paraffin embedded surgical or biopsied samples were immunohistochemically stained for MT, p53 and topoisomerase II-alpha, and performed in situ TUNEL method for evaluation of apoptotic cell ; normal control mucosa (78 cases), tubular adenomas (20 cases) and adenocarcinomas with various degree of differentiation (78 cases). RESULTS: The MT immunohistochmical reactivity was decreased in colonic adenocarcinoma than that of normal glandular epithelial and tubular adenoma, with the frequency of MT expression in colonic adenocarcinoma depending upon tumor differentiation only. But the frequency of p53 expression was correlated with T-stage, lymph node metastasis and clinical staging, while topoisomerase II-alpha expression and apoptosis in colonic adenocarcinoma were correlated with lymph node metastasis and clinical staging. The immunohistochemical expression of MT and p53 expression in colonic adenocarcinoma was inversely correlated. Also, the inverse correlation between MT expression and expression of toposiomerase II-alpha indices and apoptotic indices were noted. CONCLUSION: These data suggest that MT expression may play a role in proliferative activity and apoptosis in colonic adenocarcinoma. Although MT expression is correlated to tumor differentiation, further studies of a possibility of prognostic factor, such as p53, are required for the determination of significant relationships in other clinicinopathologic indices.

Correlation of Immunohistochemical Expression of MDR1, MRP1, Topoisomerase IIalpha with Prognostic Factors and Histoculture Drug Response Assay (HDRA) Result in Breast Carcinoma / 한국유방암학회지

PURPOSE: Drug resistance plays an important role in the failure of chemotherapy in breast cancer. The purpose of the study was to investigate the chemosensitive and chemoresistance indices of breast carcinomas and see if the in vitro chemosensitivity test correlated with the prognostic indices. METHODS: The immunohistochemical expressions of MDR1, MRP1 and topoisomerase IIalpha(topo IIalpha) were studied and then correlated these with the in vitro chemosensitivities using the histoculture drug response assay (HDRA) and clinicopathological factors in 51 breast carcinomas. RESULTS: In the breast carcinomas examined, the immunohistochemical expressions of MDR1, MRP1 and topo II alpha were strongly observed in 26 (51.0%), 16 (32.0%), 15 (31.3%) carcinomas, respectively. The MRP1 was more frequently expressed in poorly differentiated carcinomas (P= 0.006), and those of MDR1 and topo II alpha were more frequently observed in tumor overexpressing cerbB2 (P=0.038, P=0.036). The expression of MDR1 was related to that of topo II alpha (P=0.015). Comparing these markers with the in vitro chemosensitivities to cyclophosphamide, 5-FU, adriamycin, taxol and taxotere, no correlations were found between the expression of MDR1, MRP1, and topo II alpha but from the chemosensitivity using the HDRA, the growth inhibition rate for cyclophosphamide was higher in MRP1 expressing carcinomas (P=0.009). CONCLUSION: MDR1, MRP1 and topo II alpha were all found to be associated with the poor prognostic indices, but assessment of their immunohistochemical expressions did not allow for prediction of the response to chemotherapy by the in vitro chemosensitivity test in breast carcinomas.

The Immunohistochemical Expression of E2F-1 Protein and DNA Topoisomerase II-alpha E2F-1 Protein in Colorectal Cancer and Their Relationship with Clinicopathologic Factors

PURPOSE: E2F-1 is a transcriptor that converts G1 to S in the cell cycle, and Topoisomerase II-alpha is a key enzyme in the metabolism of DNA, and an indicator of cell replication. The purpose of this study was to evaluate the clinical validity of E2F-1 and Topoisomerase II-alpha as prognostic factors in colorectal cancer. METHODS: The expressions of E2F-1 and Topoisomerase II-alpha were studied immunohistochemically using tumor specimen sections fixed with formalin and paraffin-embedded for 84 cases of colorectal cancer. The correlation between E2F-1 and Topoisomerase II-alpha expressions, and their relationship with the clinicopathological factors, such as tumor differentiation, tumor invasion, lymph node metastasis and tumor stage were investigated. RESULTS: Of the 84 specimens, 43 (51.2%) were immunohistochemically negative for E2F-1, and 41 (48.8%) were positive. The expression of E2F-1 correlated with poor tumor differentiation, increased lymph node metastasis and high tumor stage. The expression of Topoisomerase II-alpha also correlated with poor tumor differentiation, increased lymph node metastasis and high tumor stage. The E2F-1 and Topoisomerase II-alpha expressions indices were significantly correlated. CONCLUSION: These results suggest that the expressions of E2F-1 and DNA Topoisomerase II-alpha may play a role as a prognostic factor for colorectal cancer, but further studies will be required for its comfirmation.

The Immunohistochemical Expression of DNA Topoisomerase II-alpha and E2F-1 in the Breast Carcinoma and Their Relationship with Clinicopathologic Factors

PURPOSE: Clinical courses of breast cancer are very different, and concern for finding a predictable marker of breast carcinomas has increased. This study focused on the relationship between the expressions of DNA topoisomerase II-alpha as a proliferative marker, and E2F-1 as a transcription factor, with clinicopathological factors of infiltrating duct carcinomas of the breast. METHODS: We investigated the expressions of E2F-1 and DNA topoisomerase II-alpha in 43 patients with infiltrating ductal carcinomas using immunohistochemical staining, and the results were analyzed with regard to clinicopathological parameters. RESULTS: Among 43 infiltrating ductal carcinomas, 24 (55.8%) were immunohistochemically negative on E2F-1 and 19 (44.2%) were positive. The expression of E2F-1 correlated with increased tumor size, positive axillary lymph node meta stasis and high stage. The topoisomerase II-alpha index correlated with increased tumor size, positive lymph node metastasis, high stage, high histological grade and negative estrogen receptor. The expression of E2F-1 and the topo II-alpha index were significantly correlated. CONCLUSION: These results suggest that the expressions of DNA topoisomerase II-alpha and E2F-1 play some role as prog nostic factors for infiltrating duct carcinomas of the breast, but much more study will be required.

Expression of c-erbB-2 Oncoprotein and DNA Topoisomerase II-alpha in Premalignant Lesions and Invasive Squamous Cell Carcinomas of the Uterine Cervix / 대한산부인과학회잡지

OBJECTIVE: The relationship was studied between expression of c-erbB-2 oncoprotein and topoisomerase II-alpha as proliferating marker in precancerous lesions and invasive squamous carcinomas of the uterine cervix. METHODS: Total 81 formalin-fixed, paraffin-embedded sections of low-grade intrasquamous lesion (22 cases), high-grade intraepithelial lesions (42 cases) and invasive squamous cell carcinomas (17 cases) in the uterine cervix were stained by immunohistochemistry for expression of the c-erbB-2 oncoprotein and topoisomerase II-alpha. RESULTS: The expression of c-erbB-2 oncoprotein and staining index (mean+/-S.D) of topoisomerase II-alpha were statistically significant between precancerous lesions and invasive carcinoma. The expression of c-erbB-2 oncoprotein has correlation with staining index (mean+/-S.D) of topoisomerase II-alpha. CONCLUSION: There results suggest that the expression of c-erbB-2 protein has relationship with progression of squamous lesions and topoisomerase II-alpha is an useful proliferating marker in the uterine cervix. And, the expression of c-erbB-2 protein has correlation with expression of topoisomerase II-alpha.

Expression of Topoisomerase II-alpha and c-erbB-2 in Breast Cancer / 한국유방암학회지

PURPOSE: Topoisomerase II-alpha is a key enzyme in DNA replication and a molecular target for many anti-cancer drugs. The C-erbB-2 oncogene (HER-2/neu) is the most frequently amplified oncogene in breast cancer. Because of the physical proximity of c-erbB-2 and topoisomerase II-alpha, co-amplification of the c-erbB-2 and topoisomerase II-alpha may occur. To investigate the clinical significance of the topoisomerase II-alpha and c-erbB-2, the correlation between topoisomerase II-alpha and c-erbB-2 was examined by immunohistochemical staining in 43 invasive ductal breast carcinomas and its relationship with other prognostic factors. METHODS: Topoisomerase II-alpha and c-erbB-2 expression was studied immunohistochemically using sections of formalin fixed, paraffin-embedded tumor specimens from 43 invasive ductal breast carcinomas. The correlation between topoisomerase II-alpha and c-erbB-2 expression, and its relationship with the clinicopathological factors such as the tumor size, lymph node metastasis, TNM stage, histological grade, nuclear grade, estrogen receptors and progesteron receptors was investigated. RESULTS: C-erbB-2 was expressed in 9 (20.9%) out of the 43 infiltrating ductal carcinoma cases. Among the prognostic factors, the tumor size, lymph node metastasis, tumor stage, nuclear grade, status of progesteron receptors and estrogen receptors did not significantly correlated with c-erbB-2 expression. The tumor size, lymph node metastasis, tumor stage, histological grade, and the absence of estrogen receptors displayed a significant relationship with the increase in the topoisomerase-alpha index. However, the topoisomerase II-alpha index did not correlate with the nuclear grade and the status of progesterone receptors. The topoisomerase II-alpha index was slightly higher in the c-erbB-2 positive expression cases compared to c-erbB-2 negative expression cases but this increase was not significant (P=0.503). CONCLUSION: These results suggest that topoisomerase II-alpha may play some role as a prognostic factor, but further investigation is needed.

Expression of Topoisomerase II-alpha and c-erbB-2 in Breast Cancer

PURPOSE: Topoisomerase II-alpha is a key enzyme in DNA replication and a molecular target for many anti-cancer drugs. The C-erbB-2 oncogene (HER-2/neu) is the most frequently amplified oncogene in breast cancer. Because of the physical proximity of c-erbB-2 and topoisomerase II-alpha, co-amplification of the c-erbB-2 and topoisomerase II-alpha may occur. To investigate the clinical significance of the topoisomerase II-alpha and c-erbB-2, the correlation between topoisomerase II-alpha and c-erbB-2 was examined by immunohistochemical staining in 43 invasive ductal breast carcinomas and its relationship with other prognostic factors. METHODS: Topoisomerase II-alpha and c-erbB-2 expression was studied immunohistochemically using sections of formalin fixed, paraffin-embedded tumor specimens from 43 invasive ductal breast carcinomas. The correlation between topoisomerase II-alpha and c-erbB-2 expression, and its relationship with the clinicopathological factors such as the tumor size, lymph node metastasis, TNM stage, histological grade, nuclear grade, estrogen receptors and progesteron receptors was investigated. RESULTS: C-erbB-2 was expressed in 9 (20.9%) out of the 43 infiltrating ductal carcinoma cases. Among the prognostic factors, the tumor size, lymph node metastasis, tumor stage, nuclear grade, status of progesteron receptors and estrogen receptors did not significantly correlated with c-erbB-2 expression. The tumor size, lymph node metastasis, tumor stage, histological grade, and the absence of estrogen receptors displayed a significant relationship with the increase in the topoisomerase-alpha index. However, the topoisomerase II-alpha index did not correlate with the nuclear grade and the status of progesterone receptors. The topoisomerase II-alpha index was slightly higher in the c-erbB-2 positive expression cases compared to c-erbB-2 negative expression cases but this increase was not significant (P=0.503). CONCLUSION: These results suggest that topoisomerase II-alpha may play some role as a prognostic factor, but further investigation is needed.

Immunohistochemical Study on the Expression of Topoisomerase II alpha and Glutathione S-Transferase pi in Acute Myeloid Leukemia / 대한임상병리학회지

BACKGROUND: Topoisomerase II (topo II) is a major target of anthracyclines and epipodophyllotoxins for anticancer treatment. The expression of topo II is low in drug resistant cell lines. High levels of glutathione S-transferase (GST)pi have been associated with emergence of cell lines resistant to alkylating agents or adriamycin. METHODS: By immunostaining with paraffin embedded bone marrow tissues, the expression of topo II alpha and GSTpi was investigated in 51 patients with acute myeloid leukemia (AML), and the relation of topo II alpha and GSTpi expression to treatment response in 29 patients with AML following induction chemotherapy was also evaluated. RESULTS: Topo II positive cells varied from less than 1% to 60% of leukemic cells and 20 (39.2%) were negative for topo II (positive cells<10%). Treatment response following chemotherapy was not related to topo II. 26 (51.0%) were positive for GSTpi. GSTpi expression was related to treatment resistance of the patients following chemotherapy. In the patients who showed both topo II alpha negative and GSTpi positive, the frequency of treatment resistance following chemotherapy was high. CONCLUSIONS: This study suggests that immunostaining of topo II alpha and GSTpi with the bone marrow paraffin sections of AML patients can be useful to predict the treatment response following chemotherapy and that further study including more patients with prospective study may substantiate topo II alpha and GSTpi as multidrug resistant markers.