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)

We present a case of a 14 year old girl with gastrointestinal stromal tumor (GIST) of the stomach. The patient discovered epigastric tumor on palpation. CT and ultrasound revealed tumor arising from the gastric wall, biopsy suggested GIST. Gastroscopically 6 cm policyclic lesion covered by unchanged mucosa has been visualized. Patient was submitted to operative management. There were no features of dissemination or invasion of surrounding structures. Stomach resection according to the Rydygier procedure has been performed. Histologically tumor arose from the muscularis propria. Mitotic activity was high 8/50. Immunohistochemical reaction against CD-117 was positive and in some parts against CD-34 which confirmed GIST. SMA and ALK were negative which excluded myogenic or inflammatory myofibroblastic tumor. Postoperative course was uneventful. There were no indications for adjuvant therapy. No recurrences were observed during follow-up.
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PMID:[Stromal tumor of the stomach in a 14 year old girl]. 1467 1

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs express KIT and have KIT mutations. Majority of these mutations cluster in the 5' end of the KIT juxtamembrane domain. Little is known about the clinicopathological profile of GIST carrying internal tandem duplications in the 3' end of KIT juxtamembrane domain (ITDs in the 3' KIT-JM). In this study, 500 immunohistochemically KIT-positive GISTs were screened for this type of mutation, and 18 cases were identified (3.6%). The majority of the ITDs consisted of 1 to 18 codon duplications, with Tyr(578), Asp(579), and Leu(576) being the most commonly duplicated codons. There were 14 gastric (78%), 2 small intestinal (11%), and 2 anal (11%) primary tumors diagnosed in 12 females and 6 males with median age of 71 years. The frequency of IDTs in gastric GISTs was 6.5% and was only 0.5% in intestinal GISTs. There was a strong female predominance (79%) among the patients with gastric tumors. Histologically, 16 GISTs were spindle cell, and 2 had epithelioid morphology. The sizes of primary tumors varied from 1 to >20 cm. Based on the combination of tumor size and mitotic activity, six tumors were classified as benign or probably benign, eight as having uncertain malignant potential, and only four as malignant. Follow-up data available in 17 patients confirmed the malignant course of disease in 3 cases. Only one of the tumors classified as potentially malignant metastasized, although the follow-up was limited in some cases. In summary, the great majority of GISTs with ITDs in the 3' KIT-JM were mitotically inactive tumors occurring predominantly in the stomach and that seemed to have a favorable course. This suggests that presence of these IDTs may define a clinicopathologically favorable subset of GISTs. The consequence of these mutations to KIT signaling should be investigated.
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PMID:Gastrointestinal stromal tumors with internal tandem duplications in 3' end of KIT juxtamembrane domain occur predominantly in stomach and generally seem to have a favorable course. 1468 27

A number of agents targeting components of pathways and processes critical to neoplastic transformation and progression are ongoing clinical development. Notable successes include imatinib mesylate (STI571, Gleevec) in Chronic Myelogenous Leukemia (CML), and Gastrointestinal Stromal Tumors (GIST) and trastuzumab (Herceptin) in HER2 amplified breast carcinoma. More recently, gefitinib (ZD1839, Iressa) and bortezomib (PS-341, Velcade) have been approved for refractory nonsmall cell lung carcinoma (NSCLC) and multiple myeloma (MM), respectively. In addition, promising results from randomized studies of bevacizumab (Avastin) and cetuximab (IMC-225, Erbitux) have been reported and shortly may lead to their approval for the treatment of colorectal carcinoma (CRC). To what degree the success or failure of these agents has been due to target, the agent, the dose or the selection of patients is uncertain. Certainly, further evaluation of these factors is required to optimize the therapeutic impact of targeted agents and imaging modalities may play a vital role in this process. The purpose of this review is to summarize recent results from trials of selected targeted agents and to suggest roles imaging may play in the further development of these and other targeted agents.
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PMID:Recent advances of molecular targeted agents: opportunities for imaging. 1468 62

The purpose of this study was to analyze the clinical features of the group of c-KIT positive GIST patients with liver metastases evaluated and treated in two referral institutions as well as to attempt to define the role of surgery in the management of GIST given the emergence to imatinib as an important part of treatment strategy in GIST patients. Between August 2001 and December 2002, 90 patients with c-KIT positive GIST were referred to our institutions. In 50 patients metastatic disease were disclosed. Of these, 35 patients (35/50; 70%) were rendered to have liver metastases and therefore offered imatinib or surgical therapy depend on CT assessment. The median follow-up of these 35 patients calculated from the time of first operation was 23 months (range 3-246 months). Male patients comprised the majority of patients (70%) with liver metastases. In 14 patients (40%) the metastases were confined only to the liver, in the others 21 patients (60%) the liver metastases were accompanied by intraperitoneal dissemination (17; 48.6%) or local recurrences (4; 11.4%). The period of time between the diagnosis of primary lesion and occurring liver metastases ranged from 0 to 164 months (median time of liver metastases presentation was 16 months for patients undergone primary curative surgery). The liver metastases were estimated as resectable in 3 cases (8.6%) and hepatic resection of all gross lesions was possible. Group of 32 patients with unresectable liver involvement was considered to treatment with imatinib. The median time of imatinib treatment for survivors is 7.5 months (range: 3.5-18.5 months). Twelve patients (37.5%) demonstrated partial response (PR) and 16 patients (50%) stable disease (SD) according to RECIST criteria. We did not observe any complete response (CR). At median follow-up 7 months, 32 of 35 patients (91.4%) were alive, 3 patients (8.6%)remained free of disease and 28 patients (87.5%) remained on imatinib treatment and have maintained disease although with partial response or stabilization only. Radical surgical resection remains the only possibility of cure for GIST patients because the complete response after imatinib therapy is restricted to a few patients only. However, despite the advanced metastatic disease, approximately 90% of patients are alive and continue imatinib treatment with median follow-up time more than 7 months. Surgery in combination with adjuvant imatinib treatment may result in improved survival with patients with advanced GIST.
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PMID:The clinical characteristics and the role of surgery and imatinib treatment in patients with liver metastases from c-Kit positive gastrointestinal stromal tumors (GIST). 1468 66

Familial gastrointestinal stromal tumor (GIST) is a rare autosomal dominant genetic disorder associated with KIT germline mutations. In sporadic forms of the disease, somatic mutations target either KIT or PDGFRA genes. In a kindred in which 5 individuals had GIST, no germline mutation in KIT coding sequence has been detected. We hypothesized that the PDGFRA gene could be a predisposing gene in familial GIST. We sequenced PDGFRA exons 12 and 18 because several somatic mutations were identified within this region. We detected a germline PDGFRA missense mutation, 2675G > T, resulting in a tyrosine substitution for the highly conserved aspartic acid at codon 846. This mutation showed perfect cosegregation with the GIST phenotype among the 7 family members tested. Interestingly, PDGFRA Asp846 is homologous to codon 820, which is located in the KIT tyrosine kinase II domain. In a previous study, a KIT germline Asp820Tyr mutation was detected in a Japanese kindred in which 6 individuals had GIST. Transfection of a KIT820Tyr complementary DNA in nude mice was found to be tumorigenic confirming the oncogenic potential of this mutation. The present study shows that PDGFRA is a second familial GIST predisposing gene. These results indicate a further example of involvement of structurally related genes in familial cancer syndromes.
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PMID:PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. 1469 10

A case for primary gastrointestinal stromal tumor (GIST) is described with reference to its ultrastructural characteristics and mutation within the exon 11 of c-kit gene. A forty-seven years old woman complaining of dysphasia was examined by endoscopy, which depicted a submucosal tumor (70 mm in diameter) with ulcerations at the fundus of the stomach. Histopathologically, the tumor cells had large nuclei and eosinophilic cytoplasm and were frequently during mitosis phase. The tumor cells were immunopositive for KIT, CD 34 and vimentin, suggesting their fibroblast-like characteristics. In contrast, desmin and S-100, a smooth muscle and an enteroglial marker, were not immunopositive within the cells. At least 30 % of the tumor cells possessed MIB-I and 20 % of them possessed p53, which are compatible with fast development of the tumor. By electron microscopy, the tumor cells possessed large oval nuclei, abundant mitochondria, caveolae and smooth endoplasmic reticulums, while no gap junctions were seen on the cells: The tumor cells thus possessed interstitial cells-like characteristics at least in part. DNA mutation search for the tumor cells however realized no gain-of-function mutation within the exon 11 of the c-kit gene, suggesting existence of other mechanism for neoplasmic growth of the tumor cells classified as gastrointestinal stromal tumors.
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PMID:A case for gastrointestinal stromal tumor (GIST) with reference to its ultrastructure and 'gain-of-function' mutation. 1471 34

The understanding of mesenchymal neoplasms of the gastrointestinal tract has evolved dramatically over the last two decades since gastrointestinal stromal tumor (GIST) was described as the most common stromal tumor arising anywhere from the esophagus to the ano-rectum. Although morphologically similar to other benign and malignant smooth muscle and neural stromal neoplasms, GIST constitutes a distinct group of rare gastrointestinal tract tumors that originate from the interstitial cells of Cajal, regulators of gut peristalsis that normally express CD117, which is the product of the c-KIT proto-oncogene that encodes a tyrosine kinase receptor that regulates cellular proliferation in GISTs. Virtually all GISTs occur from mutations of the c-KIT oncogene and exhibit consistent expression of c-KIT (CD117), which is considered the most specific criterion for a diagnosis of GIST. Gastrointestinal stromal tumors vary in their behavior and several features have to be considered to assess their malignant potential. The advent of sophisticated imaging techniques for the evaluation and sampling of stromal tumors of the gastrointestinal tract has resulted in improved detection of GISTs. The identification of a novel tumor-specific target in c-KIT resulted in the development of a tyrosine kinase-inhibitor (imatinib mesylate) that provides an encouraging option for treating GISTs. This article reviews recent advances in the understanding of the cell biology, diagnosis, and therapy of GISTS.
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PMID:Recent advances in cell biology, diagnosis, and therapy of gastrointestinal stromal tumor (GIST). 1472 14

Most gastrointestinal stromal tumors (GISTs) express constitutively activated forms of the KIT receptor tyrosine kinase protein, resulting from oncogenic mutations in the extracellular, juxtamembrane, or kinase domains. KIT oncoproteins are detected early in GIST tumorigenesis, and most GIST patients respond well to treatment with the KIT kinase inhibitor imatinib mesylate (STI571, Gleevec). However, GISTs can develop resistance to imatinib, and additional therapeutic strategies are needed. Little is known about oncogenic KIT signal transduction in GISTs, and whether the type of KIT mutation accounts for selective activation of downstream signaling intermediates. We therefore evaluated KIT downstream signaling profiles in 15 primary GISTs with mutations in KIT exons 9, 11, 13, and 17, and in two human GIST cell lines. All GISTs showed constitutive phosphorylation at KIT tyrosine residues Y703 and Y721. Additionally, most GISTs showed activation of MAPK p42/44, AKT, S6K, STAT1, and STAT3. STAT5 and JNK were not demonstrably activated in any GIST. Using GIST in vitro models, we showed that activation of MAPK p42/44, AKT, and S6K was KIT dependent, whereas STAT1 and STAT3 phosphorylation was only partially dependent on KIT activation. Correlation of activated signaling pathways with the type of KIT mutation revealed low levels of AKT phosphorylation in exon 9 mutant GISTs in contrast to a subset of GISTs with exon 11 mutations. However, additional factors are likely to modify the engagement of signaling pathways in GISTs as suggested by the fact that four GISTs with identical KIT exon 9 mutations had differential activation of MAPK p42/44 and STAT proteins. In summary, in this first report on KIT signal transduction in primary GISTs and GIST cell lines, we identified pathways that are constitutively activated in a KIT-dependent manner and therefore warrant further study as molecular targets in GISTs.
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PMID:Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). 1500 86

Most gastrointestinal stromal tumors (GISTs) contain activating mutations of the proto-oncogene c-kit. The GNNK- isoform of c-kit has a greater oncogenic potential than the GNNK+ isoform. We studied tumors from 29 patients with GIST, 19 of whom had c-kit mutations, and compared them to normal cells and HMC-1 mast cell line. c-kit transcripts were quantified by real-time PCR. The ratios of GNNK-/+ isoforms and of wild-type/mutant alleles were determined by RT-PCR and fluorometric quantification. On average, GISTs contained 1.9 times more c-kit transcripts than the HMC-1 cell line and GISTs with c-kit mutations contained 2.8 times more c-kit transcripts than those without (P=0.003). The median GNNK-/+ isoform ratios in GISTs with and without c-kit mutations were 4.4 and 4.1, respectively, and there was no difference in the GNNK-/+ ratios between the GISTs and the control samples. Both mutant and wild-type alleles of c-kit were expressed in similar amounts in 13/15 mutant GISTs. The oncogenic effects of KIT in GISTs are not related to the higher expression level of the GNNK- isoform. The high expression level of both mutated and wild-type allele transcripts of c-kit suggests that interactions between spontaneously activated and normal c-kit receptors are important in GIST tumorigenesis.
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PMID:High expression of both mutant and wild-type alleles of c-kit in gastrointestinal stromal tumors. 1506 76

Imatinib mesylate is a selective inhibitor of a few tyrosine kinases including KIT, and it is the first effective treatment for gastrointestinal stromal tumors (GISTs). We monitored the serum levels of KIT, KIT ligand (stem cell factor, SCF), and the vascular endothelial growth factor (VEGF) in patients with advanced GISTs treated with imatinib in a prospective randomized trial. Patients with GISTs (n = 66) had elevated pretreatment serum KIT and VEGF levels as compared with controls (median, 292 AU/mL [409 ng/mL] vs 238 AU/mL [333 ng/mL], P =.037; and median, 303 pg/mL vs 190 pg/mL, P =.013, respectively), but lower levels of SCF (median, 645 pg/mL vs 950 pg/mL; P < or =.0001). After 1 and 6 months of imatinib treatment the average serum KIT levels decreased 31% and 52% from pretreatment levels, whereas SCF levels increased 11% and 33%, respectively. Serum VEGF levels decreased during treatment in responding patients. The median serum SCF/KIT ratio increased with treatment duration, and was 7.7-fold higher after 12 months of treatment than at baseline (range, 3.1-259-fold). A high serum SCF/KIT ratio may increase SCF-induced cell signaling with prolonged imatinib treatment, at the time when imatinib treatment is withdrawn, and in patients whose GIST has wild-type receptors.
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PMID:Serum KIT and KIT ligand levels in patients with gastrointestinal stromal tumors treated with imatinib. 1507 Jun 66


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