Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Barrett's esophagus (BE) is a metaplastic condition caused by chronic gastroesophageal reflux which represents an early step in the development of esophageal adenocarcinoma (EAC). Single-nucleotide polymorphism microarray (SNP-chip) analysis is a novel, precise, high-throughput approach to examine genomic alterations in neoplasia. Using 250K SNP-chips, we examined the neoplastic progression of BE to EAC, studying 11 matched sample sets: 6 sets of normal esophagus (NE), BE and EAC, 4 of NE and BE and 1 of NE and EAC. Six (60%) of 10 total BE samples and 4 (57%) of 7 total EAC samples exhibited 1 or more genomic abnormalities comprising deletions, duplications, amplifications and copy-number-neutral loss of heterozygosity (CNN-LOH). Several shared abnormalities were identified, including chromosome 9p CNN-LOH [2 BE samples (20%)], deletion of CDKN2A [4 BE samples (40%)] and amplification of 17q12-21.2 involving the ERBB2, RARA and TOP2A genes [3.1 Mb, 2 EAC (29%)]. Interestingly, 1 BE sample contained a homozygous deletion spanning 9p22.3-p22.2 (1.2 Mb): this region harbors only 1 known gene, basonuclin 2 (BNC2). Real-time PCR analysis confirmed the deletion of this gene and decreased the expression of BNC2 mRNA in the BE sample. Furthermore, transfection and stable expression of BNC2 caused growth arrest of OE33 EAC cells, suggesting that BNC2 functions as a tumor suppressor gene in the esophagus and that deletion of this gene occurs during the development of EAC. Thus, this SNP-chip analysis has identified several early cytogenetic events and novel candidate cancer-related genes that are potentially involved in the evolution of BE to EAC.
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PMID:Chromosomal abnormalities and novel disease-related regions in progression from Barrett's esophagus to esophageal adenocarcinoma. 1967 Mar 30

HER-2/neu gene amplification, found in certain subtypes of (breast-) cancers, is an independent prognostic factor of poor outcome and determines eligibility for systemic treatment with trastuzumab. TopoII alpha (TOP2A) gene amplification seems to be predictive of response to a class of cytostatic agents called TopoII inhibitors, which include the anthracyclines. The observed increased efficacy of anthracyclines in HER2-positive tumors is thought to arise from the close proximity of both genes on chromosome 17, where the TopoII amplification status will determine the anthracycline sensitivity. This study aimed to validate a new polymerase chain reaction-based test, called multiplex ligation-dependent probe amplification (MLPA), as a simple and quick method to simultaneously assess HER-2/neu and TopoII alpha gene amplification status in paraffin-embedded breast cancer samples. To this end, MLPA results were compared with TopoII alpha, HER2 chromogenic in situ hybridization (CISH). We also assessed TopoII alpha protein expression by immunohistochemistry. Of 353 patients, 9% showed TopoII alpha amplification by MLPA and 13% of patients were HER2 amplified. TopoII alpha amplification was seen in 42% of HER2-amplified cases and showed no high level amplification without HER2 amplification. Eleven patients displayed TopoI alpha loss (3%). Concordance between MLPA and CISH was 91% for TopoII alpha and 96% for HER2. Correlation between amplification and overexpression of TopoII alpha was significant (P=0.035), but amplification did not always predict protein overexpression. Loss of the TopoII alpha gene was almost never associated with loss of its protein. In conclusion, MLPA is an easy and accurate method to simultaneously detect breast cancer HER-2/neu and TopoII alpha copy number status in paraffin-embedded tissue, and thus an attractive supplement or alternative to CISH.
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PMID:Simultaneous detection of TOP2A and HER2 gene amplification by multiplex ligation-dependent probe amplification in breast cancer. 1976 29

Because of the introduction of modern diagnostic methods, numerous prognostic and predictive factors have been recognized and are today considered classic, yet they seem to be insufficient in assessment of prognosis, hence the need for further investigations. Among factors newly discovered by molecular techniques, there are class I and II topoisomerases, the role of which as prognosticators has not been fully determined. The objective of the present investigation was the assessment of topoisomerase II alpha (TOP2A) expression in patients with infiltrating breast carcinoma, as a prognostic factor in correlation with other recognized prognosticators and patient survival. The study was carried out in 151 patients treated by mastectomy and lymph node excision followed by adjuvant chemotherapy. The material was evaluated histopathologically according to the pTNM system, taking into consideration such parameters as grade of malignancy (G); the ER, PR as well as HER2 and TOP2A receptors status--all of them were assessed immunohistochemically. TOP2A was expressed with varying intensity in the majority of infiltrating ductal carcinomas studied, more frequently in large T3 and T4, grade G2 and G3 tumours, in patients with extensive metastases to regional N2 and N3 lymph nodes, a positive HER2 and negative ER and PR status. Five-year mortality rates were higher and 5-year symptom-free survival rates were lower in patients with TOP2A-positive tumours as compared to individuals with a negative TOP2A status. The study indicates that TOP2A expression is a negative predictive factor and may be recognized as a prognostic factor.
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PMID:Topoisomerase II alpha--a fundamental prognostic factor in breast carcinoma. 1988 80

Copy number changes in TOP2A have frequently been linked to ERBB2 (HER2) amplified breast cancers. To study this relationship, copy number changes of ERBB2 and TOP2A were investigated by fluorescence in situ hybridization (FISH) in two cell lines; one characterized by having amplification of both genes and the other by having amplification of ERBB2 and deletion of TOP2A. The characteristics are compared to findings on paired ERBB2 and TOP2A data from 649 patients with invasive breast cancer from a previously published biomarker study. The physical localization of FISH signals in metaphase spreads from cell lines showed that simultaneous amplification is not a simple co-amplification of a whole amplicon containing both genes. Most gene signals are translocated to abnormal marker chromosomes. ERBB2 genes but not TOP2A genes are present in tandem amplicons, leading to a higher ERBB2 ratio. This observation was confirmed by patient FISH data: among 276 (43% of all patients) abnormal tumors, 67% had different ERBB2 and TOP2A status. ERBB2 amplification with normal TOP2A status was found in 36% of the abnormal tumors (15% of all patients). Simultaneous amplification of both genes was found in 28% of the abnormal tumors (12% of all patients) while TOP2A deletion and ERBB2 amplification was observed in 16% of the abnormal cases (8% of all patients). A small number of tumors had TOP2A amplification (4%) or deletion (6%) without simultaneous changes of the ERBB2 gene. ERBB2 deletion was also observed (5%) but only in tumors with simultaneous TOP2A deletion. The average gene/reference ratio was significantly different: 5.0 for TOP2A but 7.2 for ERBB2 in the amplified tumors (P<0.01). Amplification of the two genes may be caused by different mechanisms, leading to higher level of amplification for ERBB2 compared to TOP2A. In the majority of breast cancer patients, simultaneous aberration of ERBB2 and TOP2A is not explained by simple co-amplification.
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PMID:Aberrations of ERBB2 and TOP2A genes in breast cancer. 1994 23

HER2-positive breast cancers represent a distinct phenotype and are intrinsically more aggressive than HER2-negative tumors. Although HER2-targeted therapies have been rationally developed, resistance to these treatments represents a process understood poorly. There are few experimental models that allow studying the molecular mechanism of resistance. Our aim was to characterize a trastuzumab resistant breast cancer cell line (B585) that was established from an invasive ductal carcinoma. B585 grows only in immunodeficient mice as a xenograft. CGH and FISH were used to define cytogenetic alterations, gene-expression analysis and immunohistochemistry were applied to detect RNA and protein expression. By array-CGH focused amplifications were identified for C-MYC, EGFR, ErbB2, CCND1 and TOP2-A oncogenes. ErbB2 was co-amplified with TOP2-A. mRNA overexpression was detected for the amplified genes. ErbB2 protein was overexpressed and showed heterogeneous distribution. In summary, molecular cytogenetic analysis and expression profiling of B585 revealed several new alterations. Based on the experiments performed in SCID mice and the genotypic/phenotypic characteristics, this new in vivo breast cancer xenograft is a valuable model to investigate molecular mechanism of trastuzumab resistance.
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PMID:Characterization of a novel, trastuzumab resistant human breast cancer cell line. 2003 7

PURPOSE To evaluate whether the combination of HER2 with TIMP-1 (HT) or TOP2A with TIMP-1 (2T) more accurately identifies patients who benefit from cyclophosphamide, epirubicin, and fluorouracil (CEF) compared with cyclophosphamide, methotrexate, and fluorouracil (CMF) than these markers do when analyzed individually. PATIENTS AND METHODS The Danish Breast Cancer Cooperative Group (DBCG) 89D trial randomly assigned 980 high-risk Danish breast cancer patients to CMF or CEF. Archival tumor tissue was analyzed TIMP-1, and HER2-negative and TIMP-1 immunoreactive tumors were classified as HT nonresponsive and otherwise HT responsive. Similarly, the 2T panel was constructed by combining TOP2A and TIMP-1; tumors with normal TOP2A status and TIMP-1 immunoreactivity were classified as 2T-nonresponsive and otherwise 2T-responsive. Results In total, 623 tumors were available for analysis, of which 154 lacked TIMP-1 immunoreactivity, 188 were HER2 positive, and 139 had a TOP2A aberration. HT status was a statistically significant predictor of benefit from CEF compared with CMF (P(interaction) = .036 for invasive disease-free survival [IDFS] and .047 for overall survival [OS]). The 269 (43%) patients with a 2T-responsive profile had a significant reduction in IDFS events (adjusted hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P < .001) and OS events (adjusted hazard ratio, 0.54; 95% CI, 0.38 to 0.77; P < .001). 2T status was a highly significant predictor of benefit from CEF compared with CMF (P(interaction) < .0001 for IDFS and .004 for OS). CONCLUSION The 2T profile is a more accurate predictor of incremental benefit from anthracycline-containing chemotherapy than HER2, TIMP-1, or TOP2A individually, and compared with these, 2T classifies a larger proportion of patients as sensitive to anthracyclines.
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PMID:HER2, TOP2A, and TIMP-1 and responsiveness to adjuvant anthracycline-containing chemotherapy in high-risk breast cancer patients. 2043 25

Although the increasing body of knowledge in the field of immunohistochemistry and molecular biology has allowed for better understanding of the biology of breast cancer; nevertheless, a search is still in progress for new factors that would make it possible to preselect patients and employ target therapies. Predictive factors that arouse interest include topoisomerases. The authors evaluated the response to treatment and survival rates depending on expression of topoisomerase II alpha (TOP2A) and other predictive factors, as well as assessed treatment effectiveness employing therapeutic schemes based on anthracycline depending on TOP2A expression. The investigations demonstrated that the response to treatment and survival of patients with TOP2A expression were similar to the response and survival of those with tumours demonstrating the presence of other recognized predictors. The employed adjuvant therapy according to anthracycline therapeutic protocols was markedly more effective in TOP2A-positive patients as compared to the remaining individuals. Thus, TOP2A constituted a predictive factor. The study demonstrated that in adjuvant therapy employed in infiltrating ductal carcinoma of the breast, not only HER2 but also TOP2A determination in cancer cells was of importance; for this reason, routine determinations by immunohistochemistry should be performed, especially when anthracycline treatment is planned.
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PMID:Evaluation of the predictive value of topoisomerase II alpha in patients with breast carcinoma. 2006 4

The overall purpose of the study was to demonstrate applicability of the DAKO dual-color chromogenic in situ hybridization (CISH) assay (DAKO Denmark, Glostrup) with respect to 4 fluorescence in situ hybridization (FISH) probes: MYC (c-MYC), EGFR, ERBB2 (HER2), and TOP2A. The study showed that the dual-color CISH assay can convert Texas red and fluorescein isothiocyanate (FITC) signals into chromogenic signals with an almost complete 1:1 conversion ratio. Agreement studies between the FISH assays for HER2 and TOP2A and the corresponding CISH conversion assays showed 100% concordance (kappa values of 1.0) between the CISH and FISH methods for HER2 and TOP2A status. The correlations of the gene copy number to centromere-17 ratios were similarly high, with a correlation coefficient (r) for HER2 and TOP2A of more than 0.95. Owing to the relatively small number of specimens in this study, it is important that the data are confirmed in a larger study.
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PMID:Visualization of FISH Probes by dual-color chromogenic in situ hybridization. 2066 Mar 43

In breast cancer, recent studies suggest that the value of HER2 for predicting response to anthracycline-based chemotherapy may be more likely related to the concomitant amplification of the TOP2A gene. Here, we study the association between HER2 or TOP2A status and response to anthracycline-based preoperative chemotherapy and explore the interaction between HER2 or TOP2A status and intense dose-dense (IDD) chemotherapy. HER2 and TOP2A gene alterations were quantified by fluorescence in situ hybridization in primary tumor core biopsies from 373 high-risk primary breast cancer patients (tumors >/=3 cm or inflammatory) that received an IDD or conventionally scheduled anthracycline-based preoperative chemotherapy. HER2 was amplified in 94/350 tumors (27%) of which 40/94 (46%) demonstrated TOP2A amplification, and 17/94 (18%) TOP2A deletions. TOP2A gene alterations were not found in HER2 non-amplified cases. HER2 amplification was associated with a significantly higher pathologic complete response (pCR) rate only when TOP2A was co-amplified (30% vs. 11%, P = 0.002), but not when deleted (13% vs. 11%, P = 0.755), or normal (14% vs. 11%, P = 0.578) compared to HER2 non-amplified tumors. In multivariate analysis, TOP2A amplification (odds ratio [OR] 3.04, P = 0.021), but not HER2 amplification (OR 1.74, P = 0.170) was associated with a significantly higher pCR rate. No interaction was observed between HER2 or TOP2A status and IDD chemotherapy. TOP2A gene amplification may define a subset of HER2-amplified breast cancers that are responsible for the markedly improved chemosensitivity seen in HER2-positive breast cancer. However, added benefit of IDD chemotherapy itself was not associated with HER2 or TOP2A status.
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PMID:Association between HER2, TOP2A, and response to anthracycline-based preoperative chemotherapy in high-risk primary breast cancer. 2013 Sep 85

Several oncogenes and tumor-suppressor genes have been shown to be implicated in the development, progression and response to therapy of invasive breast cancer. The phenotypic uniqueness (and thus the heterogeneity of clinical behavior) among patients' tumors may be traceable to the underlying variation in gene copy number of these genes. To obtain a more complete view of gene copy number changes and their relation to phenotype, we analyzed 20 breast cancer-related genes in 104 invasive breast cancers with the use of multiplex ligation-dependent probe amplification (MLPA). We identified MYC gene amplification in 48% of patients, PRDM14 in 34%, topoisomerase IIalpha (TOP2A) in 32%, ADAM9 in 32%, HER2 in 28%, cyclin D1 (CCND1) in 26%, EMSY in 25%, IKBKB in 21%, AURKA in 17%, FGFR1 in 17%, estrogen receptor alpha (ESR1) in 16%, CCNE1 in 12% and EGFR in 9% of patients. There was a significant correlation between the number of amplified genes and the histological grade and mitotic index of the tumor. Gene amplifications of EGFR, CCNE1 and HER2 were negatively associated with estrogen receptor status whereas FGFR1, ADAM9, IKBKB and TOP2A revealed a positive association. Amplifications of ESR1, PRDM14, MYC and HER2 were associated with a high mitotic index, and PRDM14 and HER2 amplifications with high histological grade. MYC amplification was detected more frequently in ductal tumors and high-level MYC amplifications were significantly associated with large tumor size. HER2/MYC, HER2/CCNE1 and EGFR/MYC co-amplified tumors were significantly larger than tumors with either of these amplifications. Gene loss occurred most frequently in E-cadherin (CDH1) (20%) and FGFR1 (10%). In conclusion, MLPA analysis with this 'breast cancer kit' allowed to simultaneously assess copy numbers of 20 important breast cancer genes, providing an overview of the most frequent (co)amplifications as well as interesting phenotypic correlations, and thereby data on the potential importance of these genes in breast cancer.
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PMID:Molecular profiling of invasive breast cancer by multiplex ligation-dependent probe amplification-based copy number analysis of tumor suppressor and oncogenes. 2047 80


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