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)

Submucosal tumors of the gastrointestinal tract (GI tract) mainly consist of gastrointestinal mesenchymal tumors (GIMTs) that are distributed in the GI tract from the esophagus through the rectum. GIMTs include myogenic tumors, neurogenic tumors and gastrointestinal stromal tumors (GISTs). The term "GIST" is now preferentially used for the tumors that express CD34 and KIT. GIMTs are composed of spindle or epithelioid cells, and 20% to 30% show malignant behavior, including peritoneal dissemination and hematogenous metastasis. KIT expression and mutations in the c-kit gene are found only in GISTs, but not in myogenic or neurogenic tumors. Mutation in the c-kit gene is associated with aggressive features and poor prognosis, and malignant GISTs frequently have mutations in the c-kit gene. The clinicopathological features of GISTs with or without c-kit mutations are markedly different. Therefore, GIMTs may be divided into four major categories based on histochemical and genetic data: myogenic tumors; neurogenic tumors; GISTs with c-kit mutation; and GISTs without c-kit mutation. The origin of GISTs is not fully understood. However, phenotypical resemblance to the interstitial cells of Cajal (ICCs) and gain-of-function mutations in the c-kit gene may suggest origin from ICCs and/or multipotential mesenchymal cells that differentiate into ICCs.
 ...
PMID:Biological and clinical review of stromal tumors in the gastrointestinal tract. 1100 53

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, typically express the KIT protein. Activating mutations in the juxtamembrane domain (exon 11) of the c-kit gene have been shown in a subset of GISTs. These mutations lead into ligand-independent activation of the tyrosine kinase of c-kit, and have a transforming effect in vitro. Several groups have studied the clinical implication of the c-kit mutation status of exon 11 in GISTs and a possible relationship between c-kit mutations and malignant behavior has been established. Recently, a 1530ins6 mutation in exon 9 and missense mutations, 1945A>G in exon 13 of the c-kit gene were reported. The frequency and clinical importance of these findings are unknown. In this study we evaluated 200 GISTs for the presence of mutations in exons 9 and 13 of c-kit. Six cases revealed 1530ins6 mutation in exon 9 and two cases 1945A>G mutation in exon 13. All tumors with mutations in exon 9 and 13 lacked mutations in exon 11 of c-kit. None of the analyzed tumors had more than one type of c-kit mutation. All but one of the eight tumors with mutations in exon 9 or 13 of the c-kit gene were histologically and clinically malignant. All four of six cases with exon 9 mutation of which location of primary tumor was known, were small intestinal, suggesting that this type of mutation could preferentially occur in small intestinal tumors. Exon 9 and 13 mutations seem to be rare, and they cover only a small portion (8%) of the balance of GISTs that do not have mutations in exon 11 of c-kit. This finding indicates that other genetic alterations may activate c-kit in GISTs, or that KIT is not activated by mutations in all cases.
 ...
PMID:Mutations in exons 9 and 13 of KIT gene are rare events in gastrointestinal stromal tumors. A study of 200 cases. 1102 12

Gastrointestinal stromal tumors (GISTs), mesenchymal tumors largely specific for the gastrointestinal tract, have been well defined in the stomach and small intestine, but have not been extensively documented or contrasted with true smooth muscle tumors in the colon. This study was undertaken to determine the clinicopathologic features of GISTs of the colon, excluding the rectum, and to compare them with leiomyosarcomas (LMSs) of the same location. A total of 37 colonic GISTs and seven LMSs from the files of the Armed Forces Institute of Pathology and the Haartman Institute of the University of Helsinki were analyzed. The GISTs occurred predominantly in adults older than 50 years of age (median, 67 yrs), and most were histologically malignant; four small benign tumors (< or = 1 cm) were incidentally detected, and 10 others had minimal mitotic activity (five or fewer mitoses per 50 high-power fields). The colonic GISTs were typically transmural tumors with frequent intraluminal and outward bulging components. Histologically, they usually showed a spindle cell pattern (92%), whereas 8% were epithelioid. Most tumors (19 of 25) were positive for CD117 (KIT) and for CD34 (16 of 27); six tumors coexpressed alpha-smooth muscle actin and CD117; none showed desmin or S-100 protein. C-kit mutations in exon 11 were seen in 5 (36%) of 14 colonic GISTs. None of the patients with incidental small tumors had a recurrence, whereas 2 of 10 patients with tumors larger than 1 cm but minimal mitotic activity died of the disease with liver metastasis. Nearly all patients whose tumor was larger than 1 cm and showed more than five mitoses per 50 high-power fields died of disease; half had evidence of metastasis. LMSs were typically intraluminally bulging, polypoid masses that showed a histologic likeness to differentiated smooth muscle cells. They occurred in five men and two women with a median age of 61 years. Most LMSs were high-grade histologically and showed smooth muscle actin, desmin, or both. All were negative for CD34 and CD117 and lacked c-kit mutations. Five of the seven patients died of disease, and two had a long-term survival, despite high mitotic activity. These results show that KIT-positive GISTs are more common than LMSs of the colon, and these tumor groups have clinicopathologic differences that warrant their separation.
 ...
PMID:Gastrointestinal stromal tumors and leiomyosarcomas in the colon: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases. 1102 95

c-Kit is expressed in hematopoietic stem cells and plays an important role in hematopoiesis. In 16 patients with malignancies, serum-soluble c-Kit levels and the expressions of c-KIT messenger RNA (mRNA) and protein in peripheral blood mononuclear cells were analyzed serially during 26 courses of peripheral blood stem cell (PBSC) mobilization after granulocyte colony-stimulating factor administration following chemotherapy for PBSC harvest. Serum-soluble c-Kit levels were significantly lower in patients than in controls (179.7+/-17.7 arbitrary units [AU]/mL versus 274.5+/-18.9 AU/mL; P < .001), decreasing after chemotherapy (167.7+/-18.2 AU/mL), increasing from day 14, and peaking at day 19 (193.3+/-16.4 AU/mL). The numbers of both c-Kit+ cells and CD34+ cells and granulocyte-macrophage colony-forming units in peripheral blood peaked at day 17, following the peak of the expression of c-KIT mRNA. Serum-soluble c-Kit levels showed a significant positive correlation with the numbers of CD34+ cells in both peripheral blood and leukapheresis products (r = 0.553, P < .01, and r = 0.640, P < .001, respectively) and changed at higher levels in patients with large numbers of PBSCs versus patients with small numbers of PBSCs (P < .05). Serum-soluble c-Kit may reflect the capacity for hematopoiesis after chemotherapy and may be useful in predicting the number of PBSCs that can be mobilized and harvested after mobilization, as well as for monitoring the timing for PBSC harvest.
 ...
PMID:Serum-soluble c-kit levels during mobilization of peripheral blood stem cells correlate with stem cell yield. 1103 67

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the human gastrointestinal tract. Previous studies of GISTs found gain-of-function mutations of the c-kit gene, which encodes a receptor tyrosine kinase (KIT). All the mutations were confined to exon 11, which encodes the juxtamembrane domain. By further examination of the whole coding region of c-kit complementary DNA in 35 GISTs, two were found to show the identical mutation at exon 9, which encodes the extracellular domain. The aims of the present study were to examine the frequency of the extracellular domain mutation and to determine whether the mutation is a gain-of-function type or not. Genomic DNA was extracted from paraffin-embedded tissues of 133 GISTs and exon 9 of the c-kit gene was amplified by polymerase chain reaction. Screening of the mutation was carried out by single-strand conformation polymorphism analysis and direct sequencing was done. Mutant c-kit cDNA was transfected into 293T human embryonic kidney cells and the magnitude of autophosphorylation of the mutant KIT was examined with or without the ligand of KIT, stem cell factor (SCF). In total, seven GIST cases (approximately 5%) were found with the identical mutation at exon 9. The mutant KIT exhibited constitutive autophosphorylation without SCF stimulation. The prognosis of the patients with the extracellular domain mutation was comparable to that of the patients with the juxtamembrane domain mutation.
 ...
PMID:Gain-of-function mutation at the extracellular domain of KIT in gastrointestinal stromal tumours. 1127 10

Systemic mastocytosis has one unifying feature: an unexplained and pathologic increase in mast cells in specific tissues. This observation, along with clinical disease heterogeneity has long suggested that mastocytosis is a disease of complex etiology. At the same time, the last decade has witnessed significant progress in identifying the critical elements that regulate mast cell growth and development. Human mast cells are now known to arise from CD34(+) progenitors, particularly under the influence of stem cell factor (SCF). This information in turn led to the critical observation that a substantial number of patients with mastocytosis exhibit activating mutations in c-kit, the receptor for SCF. And while this observation may well be key in understanding mastocytosis, this mutation alone does not explain all heterogeneity. It now appears that other influences such as genetic polymorphisms within the host may influence the course of disease in those with KIT mutations; and that the search for additional molecular events capable of creating disease diversity must continue.
 ...
PMID:Mastocytosis: molecular mechanisms and clinical disease heterogeneity. 1137 83

Gastrointestinal stromal tumor (GIST) is currently considered to be derived from the interstitial cells of Cajal (ICC). To test the hypothesis that omental mesenchymal tumor is also a type of GIST, we evaluated the expression of specific molecules in GIST, and c-kit gene mutation in omental mesenchymal tumors, and we identified a possible counterpart of ICC in the omentum. Immunohistochemically, all of the omental mesenchymal tumors (n = 5) were positive for both KIT and CD34, and three of the five tumors were also positive for an embryonic form of smooth-muscle myosin heavy chain (SMemb). Polymerase chain reaction-single-strand conformational polymorphism analysis (PCR-SSCP) and direct sequencing revealed mutations in c-kit gene exon 11 in all five tumors. As for the ICC counterparts in the omentum, there were some KIT-positive mesenchymal cells resembling ICC at the surface of the omentum. Double fluorescence immunostaining, using anti-KIT polyclonal antibodies and monoclonal antibodies against other molecules, demonstrated that KIT-, CD34- and SMemb-positive cells were present just beneath the mesothelial cells of the omentum. These results show that omental mesenchymal tumor corresponds to GIST of the omentum, and that KIT-positive bipolar mesenchymal cells may be a counterpart of ICC in the gastrointestinal tract. Identification of a new type of KIT-positive mesenchymal cell in the omentum may lead to the discovery of a new physiological role for this organ.
 ...
PMID:Gastrointestinal stromal tumors and KIT-positive mesenchymal cells in the omentum. 1147 65

Gastrointestinal autonomic nerve tumor (GANT) is a gastrointestinal neoplasm that ultrastructurally recapitulates the enteric neural plexus. This study identifies and defines the features of 10 cases of this rare mesenchymal tumor and compares its clinicopathologic and molecular genetic features with the data on gastrointestinal stromal tumor (GIST). The majority of patients in this series presented at an older age (mean 64 years). Tumors arose from the stomach (6), small intestine (2), and retroperitoneum (2). Mean tumor size was 14 cm; however, four neoplasms were <6 cm. Histologically, tumors were spindled or epithelioid; one epithelioid tumor demonstrated a previously undescribed rhabdoid histologic phenotype. All tumors were positive for CD117 (KIT), while eight of 10 were positive for CD34. In contrast, only two were positive for S-100, and all were negative for actin and desmin. Five GANTs demonstrated GIST-specific gain-of-function mutations in the juxtamembrane domain of the c-kit gene (50%). Three of 10 patients died of disease in 22-30 months, one patient died in the postoperative period, and one patient died of complications of CML. The clinicopathologic, histologic, immunohistologic, and molecular features of GANT are similar to GIST, indicating that GANT merely represents a phenotypic variant of GIST.
 ...
PMID:Gastrointestinal autonomic nerve tumor: immunohistochemical and molecular identity with gastrointestinal stromal tumor. 1198 44

In a previous immunophenotypic molecular-based analysis it was shown that bcl2 over-expression characterizes the SS gene profile in addition to the non-random translocations. Here we show that the over-expression of an additional potentially antiapoptotic gene, the c-KIT gene, is associated with this tumour. Interestingly, whereas bcl2 over-expression appears to be restricted to the spindle cell tumoral component, c-kit mainly involves the epithelial component of biphasic SS. Twenty-three primary and metastatic samples from 21 patients were analysed by immunophenotyping (23/23), immunoprecipitations and Western blotting (3/23), and RT-PCR (23/23). Ten cases were biphasic and 13 monophasic in sub-type. Twelve, 10 and 1 case carried the SYT-SSX1, SYT-SSX2 and SYT-SSX4 fusion transcript, respectively. Co-presence of both c-Kit and SCF mRNA was observed in almost all cases (20/23), suggesting the occurrence of an autocrine loop. Immunophenotyping, confirmed by biochemical analyses, showed a modulation of c-Kit expression which was faint in the spindle and strong in the epithelial component, respectively. The study was complemented by c-Met/HGF receptor/ligand expression and c-Met protein analysis with results superimposable to those already reported. Since in each tumour, epithelial and spindle cell components harbour the same type of translocation t(X;18) the present findings suggest a shifting of the anti-apoptotic role from BCL2 to c-KIT gene during the transition from the uncommitted spindle to the differentiated epithelial cells.
 ...
PMID:c-KIT and c-KIT ligand (SCF) in synovial sarcoma (SS): an mRNA expression analysis in 23 cases. 1148 73

Imatinib mesylate, also known as STI571 or CGP57148, is a competitive inhibitor of a few tyrosine kinases, including BCR-ABL, ABL, KIT, and the platelet-derived growth factor receptors (PDGF-R). It binds to the ATP-binding site of the target kinase and prevents the transfer of phosphate from ATP to the tyrosine residues of various substrates. At oral doses of 300 mg or greater, the vast majority of patients with chronic myeloid leukaemia achieve a haematological response and this is usually associated with limited toxicity. Imatinib also has substantial activity in Philadelphia chromosome-positive acute lymphoblastic leukaemia expressing the BCR-ABL fusion protein. Gastrointestinal stromal tumours (GISTs) have also been evaluated for clinical activity of imatinib. About 90% of malignant GISTs harbour a mutation in c-kit leading to KIT receptor autophosphorylation and ligand-independent activation. According to initial clinical studies, more than 50% of GISTs respond to therapy within a few months, and only about 10-15% progress. The potential for cure and the optimal length of treatment are currently not known. Several other human cancers may over-express KIT or PDGF-R, and clinical trials to evaluate the role of imatinib in the treatment of such cancers are currently ongoing. Imatinib is an example of a specifically designed, highly targeted cancer therapy, which poses novel requirements for both pathology laboratories and clinicians in terms of identifying the major molecular mechanisms involved in tumour growth.
 ...
PMID:Tyrosine kinase inhibitor imatinib (STI571) as an anticancer agent for solid tumours. 1168 Jul 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>