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)

Although gastrointestinal stromal tumor (GIST) is the most frequent mesenchymal neoplasm of the gastrointestinal tract, until recently it has been an obscure disease. Now, there is widespread scientific and clinical interest in GIST because its principal pathogenetic defect has been identified and a specific molecular inhibitor of GIST has been developed. Most GISTs contain a gain-of-function mutation in the c-kit proto-oncogene. Mutation results in constitutive activation of the Kit receptor tyrosine kinase, which induces cellular proliferation. STI571 is an oral agent that selectively inhibits Kit. It is a landmark development in cancer treatment and marks a new era of targeted molecular therapy. Its efficacy proves that a specific inhibitor can counteract the effects of a genetic defect responsible for neoplasia. Although STI571 was first applied to GIST only 2 years ago, it has already revolutionized the treatment of patients with metastatic disease and is also currently being tested as an adjuvant therapy after the resection of primary GIST.
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PMID:The GIST of targeted cancer therapy: a tumor (gastrointestinal stromal tumor), a mutated gene (c-kit), and a molecular inhibitor (STI571). 1241 3

Gastrointestinal stromal tumours (GISTs) are the most common form of mesenchymal tumour of the gastrointestinal tract. Clinically, they range from small indolent tumours curable with surgery alone to aggressive cancers. Making a distinction between an indolent and a malignant GIST is unreliable with conventional histopathological techniques. The presence of metastases at the time of diagnosis confirms malignancy, but all GISTs should be regarded as having malignant potential. GISTs characteristically express the KIT protein, a transmembrane tyrosine kinase receptor for stem-cell factor. Most GISTs have a mutation in the KIT proto-oncogene that translates into a gain-of-function constitutive activation of the KIT kinase. KIT activation seems to be an early tumour-promoting event in pathogenesis. Commonly, malignant GISTs show high-level primary resistance to conventional chemotherapy. Imatinib mesylate is an orally administered selective inhibitor of certain tyrosine kinases including KIT. Most patients with advanced malignant GISTs achieve clinical benefit and significant antitumour responses with imatinib mesylate. Responses have been durable, and most patients tolerate the drug well at clinically effective doses. Imatinib mesylate is the first effective systemic therapy for advanced GIST.
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PMID:Management of malignant gastrointestinal stromal tumours. 1242 67

Gastrointestinal stromal tumor (GIST) is the designation for the specific c-kit expressing and Kit-signaling driven mesenchymal tumors, many of which have Kit-activating mutations. The specific identification of GIST has become increasingly important because a Kit-selective tyrosine kinase inhibitor, imatinib (Glivec, formerly known as STI571, Novartis Pharma AG, Basel, Switzerland), has shown promise as an effective adjuvant therapy treatment. GISTs are the most common mesenchymal tumors of the gastrointestinal (GI) tract. We estimate the frequency of malignant GISTs as 20% to 30% of the frequency of all soft-tissue sarcomas, but small benign tumors, often found incidentally during unrelated surgery or autopsy, are probably much more common. Older adults are most at risk for GIST; very rarely, GIST occurs in children and young adults (sometimes connected with Carney's triad), or on a familial basis. GISTs have been documented in all parts of the GI tract. A great majority of them occur in the stomach (60% to 70%) and small intestine (25% to 35%), with rare occurrence in the colon and rectum (5%), esophagus (<2%) and appendix. Some GISTs are primary in the omentum, mesentery or retroperitoneum, and are unrelated to the tubular GI tract. GISTs can be histologically identified as highly cellular spindle cell or epithelioid mesenchymal tumors, and morphology is somewhat site-dependent. However, common to all these tumors is expression of Kit (CD117 antigen), which is a major diagnostic criterion. Few other Kit-positive mesenchymal tumors of the GI tract are likely to be confused with GISTs; exceptions are metastatic melanoma and related tumors and malignant vascular tumors. Additional diagnostic criteria include common positivity for CD34 (70%), variable expression of smooth muscle actins (20% to 30%) and S100 protein (10%) and almost uniform negativity for desmin (only 2% to 4% of GISTs are positive). Although the prediction of malignancy in this tumor group is notoriously difficult, tumors that have mitotic activity counts exceeding 5 per 50 high power fields (HPF) or those larger than 5 cm have a high frequency of intra-abdominal recurrence and liver metastasis. In contrast, tumors smaller than 2 cm and those with mitotic activity counts <5 per 50 HPF are likely to be benign. These diagnostic criteria leave an inevitable gray area in the separation of benign and malignant tumors. Kit-activating mutations can be detected in at least 60% to 70% of GIST cases. Most of the mutations, in-frame deletions of several codons, are located in the juxtamembrane domain (exon 11) of the gene. Less commonly, mutations have been detected in the extracellular domain (exon 9), and tyrosine kinase domains (exons 13 and 17). Functional analysis of the different c-kit mutations and their impact on the response to tyrosine kinase inhibitors are under intense investigation.
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PMID:Pathology and diagnostic criteria of gastrointestinal stromal tumors (GISTs): a review. 1252 72

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. The concept of GIST and the definition of GIST pathology have evolved greatly over the past 5 years. GIST has been shown to share immunohistochemical, ultrastructural and histogenic similarities with the interstitial cells of Cajal. Both GIST and the interstitial cells of Cajal express KIT, the receptor tyrosine kinase that is the protein product of the c-kit proto-oncogene. KIT is universally phosphorylated in GISTs. Sequencing of c-kit complementary DNA from human GIST cells has demonstrated a high frequency of mutations that lead to constitutive activation of the KIT tyrosine kinase in the absence of stimulation by its physiologic ligand (stem cell factor). This, in turn, causes uncontrolled stimulation of downstream signaling cascades with aberrant cellular proliferation and resistance to apoptosis. Historically, malignant GIST has been highly refractory to conventional cytotoxic therapy. Signal transduction inhibition as cancer therapy was first tested successfully with imatinib mesylate (formerly known as STI571), a selective small-molecule tyrosine kinase inhibitor, with the initial target being blockade of Bcr-Abl, the oncogene with tyrosine kinase activity responsible for the pathogenesis of chronic myelogenous leukemia (CML). Imatinib was subsequently shown to block activity of the KIT tyrosine kinase as well, and in laboratory studies this led to apoptotic death of GIST cells. The first GIST patient to receive imatinib exhibited dramatic benefit despite far-advanced metastatic disease that was previously refractory to all chemotherapy. Subsequently, multicenter clinical trials have been performed to assess the safety, efficacy and biologic activity of imatinib in patients with advanced GIST. The results from these studies have established imatinib as an effective new therapeutic alternative for the majority of patients with advanced GIST, a solid tumor for which no prior chemotherapy has ever shown antitumor efficacy. This work provides proof of concept to the hypothesis that selective inhibition of aberrant signal transduction can provide important anticancer activity, if the proper signaling pathways are identified and blocked.
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PMID:Identification and treatment of chemoresistant inoperable or metastatic GIST: experience with the selective tyrosine kinase inhibitor imatinib mesylate (STI571). 1252 73

The presence of c-Kit immunoreactivity in gastrointestinal stromal tumor (GIST), currently guides treatment with the selective c-Kit inhibitor STI571 (or Gleevec) in clinical trials and establishes a precedent of immunohistochemistry-guided treatment decisions. Thus, the optimization of detection conditions for c-Kit and the determination of its incidence in other malignancies have clinical bearing. Aims of our study were: 1) to determine the incidence of c-Kit expression in formalin-fixed paraffin-embedded tissue (FFPE) in pulmonary small cell carcinoma (SCC) and non small cell carcinoma (NSCC), pulmonary carcinoid, and malignant mesothelioma (MM); and 2) to test the feasibility of c-Kit determination using commercially available antibodies and routine immunohistochemical settings, comparing the performance of two commercially available antibodies, Dako and Santa Cruz. The Dako antibody detected positive stain in 10/22 SCC, 3/8 carcinoids, 1/57 NSCC (1/30 adenocarcinomas, 0/24 squamous cell carcinomas, 0/3 large cell undifferentiated carcinomas), and 7/33 MM. The Santa Cruz antibody detected c-kit in 8/22 SCC, 0/57 NSCC, 1/8 carcinoids, and 0/33 MM. HIER increased the performance of both antibodies. We conclude that c-Kit can routinely be detected in FFPE tissue with commercially available antibodies, and that the Dako anti-c-Kit has a higher sensitivity than the Santa Cruz antibody. C-Kit expression is common in SCC and carcinoids, very rare in NSCC, and infrequent in MM. The frequent c-Kit expression in SCC highlights that this molecule plays an important role in the biology of this malignancy, and that it could be targeted in subsets of patients for therapy with c-Kit inhibitors.
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PMID:Immunohistochemistry frequently detects c-Kit expression in pulmonary small cell carcinoma and may help select clinical subsets for a novel form of chemotherapy. 1261 Mar 57

A 69-year-old man presented with a malignant gastrointestinal stromal tumor associated with secondary amyloidosis. The tumor had classic features of a malignant gastrointestinal stromal tumor with interlacing fascicles and whorls of spindled cells, numerous and conspicuous mitotic figures, and extensive coagulative necrosis. The cells stained diffusely for CD117 (c-Kit), confirming the diagnosis of gastrointestinal stromal tumor. The spleen, 1 adrenal gland, and part of the pancreas were removed en block with the stomach. By microscopy, the spleen and adrenal gland were partially replaced with amyloid deposits confirmed by Congo red staining, electron microscopy, and immunohistochemistry. In contrast, neither the tumor nor the surrounding vasculature showed amyloid deposition. To our knowledge, this represents only the second case of systemic amyloidosis associated with a gastrointestinal stromal tumor. This case is unique in that extensive, diffuse amyloid deposits were observed in the spleen, adrenal gland, and liver.
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PMID:Secondary amyloidosis and gastrointestinal stromal tumors. A case report and discussion of pathogenesis. 1268 77

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

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal (GI) tract. The c-kit receptor tyrosine kinase (KIT) is expressed by practically all GISTs, and gain-of-function mutations of KIT are present in most GISTs. Interstitial cells of Cajal (ICC) are the pacemaker of the peristaltic movement of the GI tract. Since signals through KIT are essential for development of ICC and since multiple GISTs develop from the hyperplastic lesion of ICCs in familial GIST patients with germline mutations of KIT, GISTs are considered to originate from ICC. Imatinib mesylate, which was developed for treatment of chronic myeloid leukemia (CML), was found to be useful for treatment of GISTs. Imatinib mesylate inhibits BCR-ABL fused tyrosine kinase that causes CML. Imatinib mesylate also inhibits the mutated KIT observed in most GISTs, and this explains the effectiveness of Imatinib mesylate on GISTs. GISTs appear to serve as a model for molecule-based diagnosis and treatment of solid tumors.
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PMID:Gastrointestinal stromal tumors (GIST): a model for molecule-based diagnosis and treatment of solid tumors. 1282 97

Primary neoplasms of the greater omentum are rare. We report a case of omental tumors occurring in 58-year-old Japanese man. Ultrasonography showed multiple solid tumors in the abdomen and angiography identified the greater omentum as the precise location. The tumors were completely resected with the major part of the greater omentum and analyzed histologically, immunohistochemically, and genetically. Positive reactivity for CD117 (c-kit, a transmembrane tyrosine kinase receptor) and CD34, and the absence of TLS/FUS-CHOP rearrangement confirmed that the tumors were extragastrointestinal counterparts of a gastrointestinal stromal tumor. Although the higher mitotic activity measured by the Ki-67 labeling ratio suggests the malignant potential of this tumor, there was no recurrence at the 20-month follow-up.
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PMID:Extragastrointestinal stromal tumor of the greater omentum: case report and review of the literature. 1282 62

The specific c-kit protein (CD117)-positive gastrointestinal stromal tumor (GIST) of the rectum has been sporadically reported in pathology literature, but its radiologic features have never been thoroughly described. We present 2 cases of histologically and immunohistochemically confirmed rectal GISTs. Their clinical and multimodality imaging features are illustrated, and the relevant literature is reviewed and discussed.
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PMID:Gastrointestinal stromal tumor of rectum: a report of 2 cases. 1288 52


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