Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Gastrointestinal stromal tumors (GIST) are caused by activating mutations in the KIT or platelet-derived growth factor receptor alpha receptor tyrosine kinase genes. Approximately 85% of GIST patients treated with imatinib mesylate achieve disease stabilization, however, often in the presence of residual tumor masses. Complete remissions are rare and a substantial proportion of patients develop resistance to imatinib. Our study was designed to determine whether imatinib-associated responses may account for these clinical findings. We report here that imatinib stimulates cellular quiescence in a proportion of GIST cells as evidenced by up-regulation of the CDK inhibitor p27(Kip1), loss of cyclin A, and reduced BrdUrd incorporation. Mechanistically, these events are associated with an imatinib-induced modulation of the APC/CDH1 signaling axis. Specifically, we provide evidence that imatinib down-regulates SKP2 and that this event is associated with increased nuclear CDH1, an activator of the APC that has been shown to regulate SKP2 stability. We also show that those GIST cells that do not undergo apoptosis in response to imatinib overexpress nuclear p27(Kip1), indicating that they have withdrawn from the cell cycle and are quiescent. Lastly, we provide evidence that a fraction of primary GISTs with high SKP2 expression levels may have an increased risk of disease progression. Taken together, our results support a model in which GIST cells that do not respond to imatinib by apoptosis are removed from the proliferative pool by entering quiescence through modulation of the APC/CDH1-SKP2-p27(Kip1) signaling axis. These results encourage further studies to explore compounds that modulate this pathway as antitumor agents in GISTs.
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PMID:Imatinib mesylate induces quiescence in gastrointestinal stromal tumor cells through the CDH1-SKP2-p27Kip1 signaling axis. 1897 47

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal tract. Approximately 85% of GISTs harbor activating mutations in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene and approximately 95% of GISTs are positive for KIT (CD117) by immunohistochemistry. Nevertheless, approximately 5% of GISTs lack KIT expression. Inhibition of KIT and PDGFRA by tyrosine kinase inhibitors has revolutionized the treatment of GISTs and demands accurate tumor classification. DOG1.1 is a recently described mouse monoclonal antibody reported to have superior sensitivity and specificity compared with KIT (CD117) and CD34. We evaluated this new antibody on a group of 81 GISTs obtained from 74 patients with special regard to KIT-negative GISTs (n=28), pediatric GISTs (n=11), and GISTs associated with neurofibromatosis type I (NF1) (n=16). Conventional GISTs (n=26) were also included. All conventional KIT-positive GISTs, all NF1-associated GISTs, and 9/11 pediatric GISTs expressed DOG1.1. DOG1.1 was expressed in 10/28 (36%) of KIT-negative tumors. The staining pattern was cytoplasmic and/or membranous. This study demonstrates that DOG1.1 is a sensitive immunohistochemical marker for GIST, comparable with KIT, with the additional benefit of detecting 36% of KIT-negative GISTs. DOG1.1 is also a sensitive marker for unusual GIST subgroups lacking KIT or PDGFRA mutations. In tumors that are negative for both KIT and DOG1.1, mutational screening may be required to confirm the diagnosis of GIST.
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PMID:Monoclonal antibody DOG1.1 shows higher sensitivity than KIT in the diagnosis of gastrointestinal stromal tumors, including unusual subtypes. 1901 64

The author reports a very rare case of a gastrointestinal stromal tumor in the uterus. A 74-year-old woman was admitted to our hospital because of pelvic pain. Imaging modalities showed a large tumor of the posterior aspect of the uterus, and enucleation was performed. The tumor was attached to the posterior uterus, similar to subserosal leiomyoma. No attachment to the gastrointestinal organs was recognized. The tumor was soft, tan, and measured 13 x 15 x 12 cm. The tumor consisted of cellular spindle cells with focal necrotic areas. Mitotic figures were noted in 3 of 50 high-power fields. The tumor cells were positive for KIT, CD34, platelet-derived growth factor receptor alpha, and vimentin, but negative for alpha-smooth muscle actin, S100 protein, p53 protein, HMB45, and desmin. Ki-67 labeling was 3%. Five normal uteruses used as controls showed KIT-positive Cajal-like mesenchymal cell scattering in the myometrium. Genetic analyses of the c-kit gene (exons 9, 11, 13, and 17) and platelet-derived growth factor receptor alpha gene (exons 12 and 18) revealed a point mutation at codon 559 (GTT-->GAT) of exon 11 of the c-kit gene. Other exons showed no abnormalities. This case shows that gastrointestinal stromal tumor may occur in the uterus.
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PMID:Gastrointestinal stromal tumor of the uterus: a case report with genetic analyses of c-kit and PDGFRA genes. 1904 11

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Activating mutations in tyrosine kinase receptors KIT or platelet-derived growth factor receptor alpha (PDGFRA) are the main mechanisms causing the disease. Patients generally present with non-specific symptoms, while a number of tumors are discovered incidentally and may be metastatic at the time of diagnosis. Aggressive GISTs have a defined pattern of metastasis to the liver or throughout the abdomen, or both. Though GISTs rarely present systemic or isolated paraneoplastic reactions, a few cases have been reported in the literature. We present the case of a 54-year-old patient with metastatic GIST at diagnosis and the emergence of paraneoplastic manifestations during follow-up.
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PMID:Unusual combination of paraneoplastic manifestations in a patient with metastatic gastrointestinal stromal tumor (GIST). 1908 69

We report 2 cases of a distinctive neoplasm arising from Bartholin gland and presenting as a vulval or vaginal mass. The tumors occurred in patients aged 44 and 51 years and were 2 and 3 cm in maximum dimension. In both cases, normal Bartholin gland tissue was identified adjacent to the lesion. The neoplasms were unencapsulated and largely well circumscribed but with a focally infiltrative edge. They were composed of tubular, trabecular, or insular arrangements with a double layer of inner cuboidal cells with round nuclei and outer cells with ovoid nuclei and clear cytoplasm, corresponding to epithelial and myoepithelial cells, respectively. Luminal eosinophilic colloid-like material was present. In both cases, a minor proportion of the neoplasm consisted of cribriform arrangements, creating an appearance reminiscent of adenoid cystic carcinoma, although the overall morphology was not typical of that lesion. Mitotic figures were identified in both cases, the mitotic count being 1 and 5/10 high-power fields. Immunohistochemically, the inner cells were positive with epithelial markers, including broad-spectrum cytokeratins and epithelial membrane antigen, and the outer cell layer was positive with myoepithelial markers p63, calponin, and alpha-smooth muscle actin. Both neoplasms exhibited diffuse strong immunoreactivity of the epithelial cells with c-kit. Activating mutations in KIT exons 9, 11, 13, and 17 and in platelet-derived growth factor receptor alpha exons 12, 14, and 18 were searched for by polymerase chain reaction and direct sequencing but were not identified. We believe this represents a low-grade carcinoma arising from Bartholin gland composed of a dual population of epithelial and myoepithelial cells and closely resembling the salivary gland neoplasm termed epithelial-myoepithelial carcinoma. We propose the term low-grade epithelial-myoepithelial carcinoma of Bartholin gland.
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PMID:Low-grade epithelial-myoepithelial carcinoma of bartholin gland: report of 2 cases of a distinctive neoplasm arising in the vulvovaginal region. 1962 Sep 48

A great majority of gastric mesenchymal tumors are gastrointestinal stromal tumor (GIST). A rare group of non-GISTs include myxoid mesenchymal neoplasms. In this report, we describe 12 cases of a distinctive gastric tumor, named here as plexiform fibromyxoma. These tumors occurred in 5 men and 7 women of ages 7 to 75 years (median, 41 y). All tumors were located in the gastric antrum and 6 of them also extended into extragastric soft tissues or into the duodenal bulb. The tumors measured from 3 to 15 cm (median, 5.5 cm). Histologically typical was a plexiform intramural growth with multiple micronodules containing paucicellular to moderately cellular myxoid to collagenous and fibromyxoid neoplastic elements. A prominent, sometimes plexiform capillary pattern was typically present. Extramural components included subserosal nodules, and sometimes more cellular, solid nonplexiform spindle cell proliferation. The tumor cells varied from oval to spindled and had limited atypia and mitotic activity < 5/50 high-power fields. Frequent ulceration, mucosal invasion, and vascular invasion (4 cases) had no adverse significance in these tumors. Immunohistochemically, the tumor cells were positive for alpha smooth muscle actin, and variably for CD10, and were consistently negative for KIT, DOG1, CD34, desmin, and S100 protein. No KIT or platelet-derived growth factor receptor alpha mutations were present in the 3 examined cases. None of the 4 patients who were followed from 9 to 20 years (median, 19 y) developed recurrences or metastases. Additional 3 patients survived 14 to 25 years with unknown tumor status. Review of large numbers of mesenchymal tumors in the esophagus and intestines did not reveal similar tumors. Plexiform fibromyxoma is a distinctive benign gastric antral neoplasm that should be separated from GIST, nerve sheath tumors, and other fibromyxoid neoplasms.
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PMID:Plexiform fibromyxoma: a distinctive benign gastric antral neoplasm not to be confused with a myxoid GIST. 1967 52

Medulloblastomas (MB) and primitive neuroectodermal tumors (PNET) are the most common malignant brain tumors in children. These two tumor types are histologically similar, but have different genetic backgrounds and clinical outcomes. Other brain tumors, such as gliomas, frequently have coamplification and overexpression of receptor tyrosine kinases KIT, platelet-derived growth factor receptor alpha (PDGFRA), and vascular endothelial growth factor receptor 2 (VEGFR2). We investigated protein expression and gene copy numbers of KIT, PDGFRA, and VEGFR2 in 41 MB and 11 PNET samples by immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH). KIT and PDGFRA expression was detected in both MBs and PNETs, whereas VEGFR2 expression was weak in these tumors. KIT, PDGFRA, and VEGFR2 amplifications were all present in 4% of MBs/PNETs, and KIT amplification was associated with concurrent PDGFRA and VEGFR2 amplifications (P <or= 0.001). Most strikingly, increased gene copy number of PDGFRA was associated with poor overall survival (P = 0.027). We suggest that coamplification of PDGFRA or VEGFR2 with KIT may be clinically useful novel molecular markers in MBs and PNETs.
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PMID:Amplification and overexpression of KIT, PDGFRA, and VEGFR2 in medulloblastomas and primitive neuroectodermal tumors. 1977 61

This report presents a case of multiple gastrointestinal stromal tumors (GIST) with neurofibromatosis type 1 (NF1). A 68-year-old woman was admitted to the hospital because of a tumor close to the head of the pancreas. Imaging studies revealed submucosal tumors of the duodenum. The retroperitoneal tumor was diagnosed before surgery. Besides the main tumor in the duodenum, multiple small submucosal tumors were found in the duodenum and upper part of the jejunum during the operation. All of these tumors were resected. The histological diagnosis of all these tumors was GISTs. These tumors were immunohistochemically positive for KIT, but they demonstrated no mutation in c-kit exons 9, 11, 13, and 17, and platelet-derived growth factor receptor alpha exons 12 and 18. No recurrence occurred for a year after surgery.
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PMID:Multiple gastrointestinal stromal tumors in neurofibromatosis type 1: report of a case. 1988 21

Biopsies and cell lines of natural killer/T-cell lymphoma, nasal type (NKTCL) were subject to combined gene expression profiling and array-based comparative genomic hybridization analyses. Compared with peripheral T-cell lymphoma, not otherwise specified, NKTCL had greater transcript levels for NK-cell and cytotoxic molecules, especially granzyme H. Compared with normal NKcells, tumors were closer to activated than resting cells and overexpressed several genes related to vascular biology, Epstein-Barr Virus-induced genes, and PDGFRA. Notably, platelet-derived growth factor receptor alpha and its phosphorylated form were confirmed at the protein level, and in vitro the MEC04 NKTCL cell line was sensitive to imatinib. Deregulation of the AKT, Janus kinase-signal transducers and activators of transcription, and nuclear factor-kappaB pathways was corroborated by nuclear expression of phosphorylated AKT, signal transducers and activators of transcription 3, and RelA in NKTCL, and several deregulated genes in these pathways mapped to regions of recurrent copy number aberrations (AKT3 [1q44], IL6R [1q21.3], CCL2 [17q12], TNFRSF21 [6p12.3]). Several features of NKTCL uncovered by this analysis suggest perturbation of angiogenic pathways. Integrative analysis also evidenced deregulation of the tumor suppressor HACE1 in the frequently deleted 6q21 region. This study highlights emerging oncogenic pathways in NKTCL and identifies novel diagnostic and therapeutic targets.
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PMID:Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type. 1996 20

Gastrointestinal stromal tumour (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. GISTs are believed to originate from intersticial cells of Cajal (the pacemaker cells of the gastrointestinal tract) or related stem cells, and are characterized by KIT or platelet-derived growth factor receptor alpha (PDGFRA) activating mutations. The use of imatinib has revolutionized the management of GIST and altered its natural history, substantially improving survival time and delaying disease progression in many patients. The success of imatinib in controlling advanced GIST led to interest in the neoadjuvant and adjuvant use of the drug. The neoadjuvant (preoperative) use of imatinib is recommended to facilitate resection and avoid mutilating surgery by decreasing tumour size, and adjuvant therapy is indicated for patients at high risk of recurrence. The molecular characterization (genotyping) of GISTs has become an essential part of the routine management of the disease as KIT and PDGFRA mutation status predicts the likelihood of achieving response to imatinib. However, the vast majority of patients who initially responded to imatinib will develop tumour progression (secondary resistance). Secondary resistance is often related to secondary KIT or PDGFRA mutations that interfere with drug binding. Multiple novel tyrosine kinase inhibitors may be potentially useful for the treatment of imatinib-resistant GISTs as they interfere with KIT and PDGFRA receptors or with the downstream-signalling proteins.
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PMID:Imatinib treatment for gastrointestinal stromal tumour (GIST). 1996 34


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