Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study we analyzed the clinicopathologic features of duodenal smooth muscle or stromal tumors, including 156 GISTs, 6 leiomyomas (LMs), and 5 leiomyosarcomas (LMSs) from the files of the Armed Forces Institute of Pathology and the Haartman Institute of the University of Helsinki. GISTs were documented as KIT positive (n = 109); 47 tumors were also included because of their histologic identity to KIT-positive cases. GIST-specific c-kit gene mutations were documented in exon 11 in 9 of 30 cases (30%) and exon 9 in 4 of 30 cases (13%). The GISTs occurred in patients with an age range of 10-88 years (median 56 years); 54% were male. Ten patients had neurofibromatosis type I; six of them had multiple GISTs. The GISTs ranged from small asymptomatic intramural or external nodules to large masses that extended into the retroperitoneum (median size 4.5 cm). They were mostly spindle cell tumors; three malignant GISTs had an epithelioid morphology, and 81 cases had skeinoid fibers. The tumors often coexpressed CD34 and KIT (54%) and were variably positive for smooth muscle actin (39%) and S-100 protein (20%) but never for desmin. A total of 86% of patients with tumors >5 cm with >5 mitoses/50 high power fields (HPF) (n = 21) died of disease, whereas no tumor <2 cm with <5 mitoses/50 HPF (n = 12) recurred or caused death. Long latency was common between primary operation and recurrences or metastases; either one occurred in 49 of 140 patients with follow-up (35%). No formula could accurately predict metastases, which occasionally developed even if mitotic activity was <5/50 HPF and size <5 cm. Metastases were in the abdominal cavity, liver, and rarely in bones and lungs but never in lymph nodes. Four actin- and desmin-positive and KIT-negative benign intramural LMs were similar to those more often seen in the esophagus. There were five LMSs, one of which formed a polypoid intraluminal mass; all were actin positive and KIT negative. The great majority of duodenal mesenchymal tumors are GISTs, which have a spectrum from small indolent tumors to overt sarcomas. LMs and LMSs are rare.
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PMID:Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the duodenum: a clinicopathologic, immunohistochemical, and molecular genetic study of 167 cases. 1271 47

The sensory receptors for hearing and balance are the hair cells of the cochlea and vestibular organs of the inner ear. Permanent hearing and balance deficits can be triggered by genetic susceptibilities or environmental factors such as infection. Unlike mammalian hair cells that have a limited capacity for regeneration, the vestibular organ of the avian ear is constantly undergoing hair cell regeneration, whereas the avian cochlea undergoes regeneration only when hair cells are damaged. In order to gain insights into the genetic programs that govern the regenerative capacity of hair cells, we interrogated custom human cDNA microarrays with sensory epithelial cell targets from avian inner ears. The arrays contained probes from conserved regions of approximately 400 genes expressed primarily in the inner ear and approximately 1500 transcription factors (TF). Highly significant differences were observed for 20 inner-ear genes and more than 80 TFs. Genes up-regulated in the cochlea included BMP4, GATA3, GSN, FOXF1 and PRDM7. Genes up-regulated in the utricle included SMAD2, KIT, beta-AMYLOID, LOC51637, HMG20B and CRIP2. Many of the highly significant changes were validated by Q-PCR and in situ methods. Some of the observed changes implicated a number of known biochemical pathways including the c-kit pathway previously observed in melanogenesis. Twenty differentially expressed TFs map to chromosomal regions harboring uncloned human deafness loci, and represent novel candidates for hearing loss. The approach described here also illustrates the power of utilizing conserved human cDNA probes for cross-species comparisons.
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PMID:Gene expression differences in quiescent versus regenerating hair cells of avian sensory epithelia: implications for human hearing and balance disorders. 1276 Oct 41

Expression and gain-of-function mutation of the c-kit gene, that encodes a receptor tyrosine kinase (KIT), have been reported in mast cell tumors and gastrointestinal stromal tumors (GISTs). Among human testicular germ cell tumors (GCTs), seminomas and seminoma components of mixed GCTs have also been shown to express KIT, but only one study has found the c-kit gene mutation at exon 17 in seminoma. To elucidate the frequency and location of the c-kit gene mutation of testicular GCTs, we analyzed the whole coding region of the c-kit complementary DNA along with 4 mutational hot spots (exons 9, 11, 13 and 17) of the c-kit genomic DNA by polymerase chain reaction and direct sequencing. Somatic mutations were found in 4 pure seminomas of 34 testicular GCTs (11.8%). One mutation was found in exon 11 (W557R) and the others were observed in exon 17 (D816H and D816V). These types of mutations were reported in GISTs (W557R), seminoma (D816H) and mastocytosis (D816V) and were considered to be gain-of-function mutations, although there were no differences of any clinicopathological factors or outcome between patients with and without mutations. Additionally, we also demonstrated coexpression of Gly-Asn-Asn-Lys510-513 (GNNK) + and GNNK - isoforms of the c-kit gene with dominance of the GNNK - transcript in all testicular GCTs. The mutations and/or preferential expression of GNNK - isoform of the c-kit gene might play an important role in the development of testicular GCTs, and these tumors may also be targets for STI571, which is a promising drug for advanced and metastatic GISTs.
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PMID:Alterations of the c-kit gene in testicular germ cell tumors. 1282 71

Overexpression of KIT protein (CD117), the product of the c-kit gene, has been shown to have important prognostic and therapeutic implications for a number of malignant neoplasms. Previous studies have shown conflicting results regarding the expression of c-kit in malignant mesothelioma. To determine whether malignant mesothelioma expresses KIT, immunohistochemistry and RT-PCR were used to analyze archived tissue from 37 cases of mesothelioma. Although a subset of mesotheliomas demonstrated specific staining with the DAKO anti-KIT antibody, in each case staining was nuclear. We could not detect c-kit mRNA by a sensitive RT-PCR assay, even in cases with strong nuclear staining. Furthermore, a second anti-KIT antibody (Cell-Marque) only demonstrated staining in a single mesothelioma case and in none of the cases that demonstrated nuclear staining. We conclude that immunoreactivity for KIT in mesothelioma does not represent expression of the c-kit gene and may represent antibody cross-reaction with nuclear proteins. Our results raise doubt about previously reported expression of KIT in mesothelioma and consequently, the applicability of therapeutic agents that target the kinase activity of KIT.
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PMID:c-Kit is not expressed in malignant mesothelioma. 1526 10

Gastrointestinal stromal tumors (GIST) are composed of KIT-positive mesenchymal-origin spindle- or polygonal-shaped tumor cells in the gastrointestinal tract without immunoreactivity for desmin and S-100. The gain-of-function mutations in the c-kit gene (90%) or platelet-derived growth factor receptor alpha (PDGF-R alpha) gene (5%) are now considered to be causative for GIST. STI571 (Glivec), a molecule designed to selectively inhibit Bcr-Abl, KIT, and PDGF-R activity, shows high response rate and efficacy for non-resectable and/or relapsed GIST (PR 60%). Its serious adverse effects (more than Grade 3) were infrequent, thus, tolerability and safety are good. Glivec is the first successful case of molecular target therapy for solid tumors. However, new resistance against this new generation of drug is going to appear and becomes an urgent problem.
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PMID:[Target-based therapy against gastrointestinal stromal tumors--from molecular diagnosis to molecular target therapy]. 1293 60

Mutations in the proto-oncogene c-kit cause constitutive kinase activity of its product, KIT protein, and are associated with human mastocytosis and gastrointestinal stromal tumors (GISTs). Although currently available tyrosine kinase inhibitors are effective in the treatment of GISTs, there has been limited success in the treatment of mastocytosis. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a benzoquinoid ansamycin antibiotic, which binds to heat shock protein 90 (hsp90) causes destabilization of various hsp90-dependent kinases important in oncogenesis. Treatment with 17-AAG of the mast cell line HMC-1.2, harboring the Asp816Val and Val560Gly KIT mutations, and the cell line HMC-1.1, harboring a single Val560Gly mutation, causes both the level and activity of KIT and downstream signaling molecules AKT and STAT3 to be down-regulated following drug exposure. These data were validated using Cos-7 cells transfected with wild-type and mutated KIT. 17-AAG promotes cell death of both HMC mast cell lines. In addition, neoplastic mast cells isolated from patients with mastocytosis, incubated with 17-AAG ex vivo, are selectively sensitive to the drug compared to the mononuclear fraction. These data provide compelling evidence that 17-AAG may be effective in the treatment of c-kit-related diseases including mastocytosis, GISTs, mast cell leukemia, subtypes of acute myelogenous leukemia, and testicular cancer.
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PMID:17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells. 1455 Nov 38

Although their overall incidence is uncommon, gastrointestinal stromal tumors (GIST) are the most frequently encountered mesenchymal tumors of the GI tract. Their pathology has been recently defined by the presence of KIT (transmembrane receptor tyrosine kinase). The majority of GISTs have c-kit gain-of-function mutations mainly in exon 11 (highly conserved juxtamembrane region) that eventuates in constitutive activation of KIT, promoting proliferation and antiapoptotic signaling. Imatinib mesylate (Gleevec) is a specific inhibitor of KIT kinase activation, and in phase II clinical trials has proven to be remarkably efficacious in heavily pretreated GIST patients with advanced disease. The molecular and genomic determinants of response/resistance patterns are the subject of ongoing studies, and adjuvant studies are also under way. The initial evaluations of imatinib provide proof of concept for the hypothesis-driven design of selective molecularly targeted therapies for solid tumor malignancies.
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PMID:Imatinib mesylate: a molecularly targeted therapy for gastrointestinal stromal tumors. 1468 11

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

This phase 2 pilot study was conducted to determine the efficacy and safety of imatinib mesylate in patients with c-kit-positive acute myeloid leukemia (AML) refractory to or not eligible for chemotherapy. Twenty-one patients were enrolled and received imatinib 600 mg orally once daily. Five responses were seen primarily in patients, starting with relatively low blast counts in bone marrow (BM) and peripheral blood (PB): 2 patients who were considered refractory on chemotherapy on the basis of persistence of blasts in PB and BM met the criteria for complete hematologic remission, 1 patient had no evidence of leukemia, and 2 patients achieved a minor response. Treatment with imatinib demonstrated a good safety profile and was well tolerated. Western blot analysis and immunohistochemistry demonstrated c-Kit activation in primary AML cells. Further, imatinib treatment of primary AML cells inhibited c-Kit tyrosine-phosphorylation. Genomic DNA-sequencing of c-KIT showed no mutations in exons 2, 8, 10, 11, 12, and 17. Although some of the responses derived from relatively small reductions in leukemic blasts and may be attributable, in part, to prior chemotherapy, these cases suggest that imatinib has interesting clinical activity in a subset of patients with c-kit-positive AML. Further clinical trials are warranted to explore the clinical potential of imatinib in AML and to identify the underlying molecular mechanism.
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PMID:Efficacy and safety of imatinib in adult patients with c-kit-positive acute myeloid leukemia. 1563 13

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


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