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

Mast cell disease (MCD) is characterized by the abnormal growth and accumulation of neoplastic mast cells (MC) in one or more organs. The diagnosis of systemic MCD is most commonly established by a thorough histological and immunohistochemical examination of a bone marrow (BM) trephine specimen. In cases with pathognomonic perivascular and -trabecular aggregates of morphologically atypical MC and significant BM involvement, the diagnosis may be relatively straightforward. In contrast, when a sparse, loose pattern of MC infiltration predominates, or when MCs are obscured by an associated non-MC hematological neoplasm, a high index of suspicion and use of adjunctive tests, including special stains, such as tryptase and CD25, may be necessary to reach a diagnosis. The updated classification for MCD clarifies the clinical and pathological criteria for categorizing patients into relatively discrete subgroups. Some cases, however, such those with Fip1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA)(+) clonal eosinophilia associated with elevated serum tryptase levels, with features that overlap MCD and chronic eosinophilic leukemia, may not be easy to categorize on the basis of this classification. There is no standard therapy for MCD and treatment has to be tailored to the needs of the individual patient. MC-cytoreductive therapies, such as interferon-alpha and chemotherapy, are generally reserved for patients with progressive disease and organopathy. A subset of MCD patients with associated eosinophilia who carry the FIP1L1-PDGFRA oncogene will achieve complete clinical, histological, and molecular remissions with imatinib mesylate therapy, in contrast to those with c-kit D816V mutations. The BM pathology, consensus classification, and current therapies for MCD are further discussed in this article.
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PMID:Systemic mastocytosis: bone marrow pathology, classification, and current therapies. 1599 24

A 12-year-old girl presented with a large abdominal tumor. At surgery, a huge pedunculated extraluminal tumor was found arising from the greater curvature of the stomach and invading the surrounding structures, and there were also a submucosal tumor measuring 5 x 4 x 4 cm and multiple intramural nodules beside the main tumor. These lesions, which were removed with 1.0-cm surgical margins, were immunohistochemically positive for c-kit (CD117) and CD34. A diagnosis of gastrointestinal stromal tumor (GIST) was made. The huge size of the tumor (3.6 kg in weight and 36 x 25 x 25 cm in diameter), the invasion of the surrounding structures, and the increased mitotic figures indicated the GIST had malignant potential. Sequence analysis of the polymerase chain reaction product of RNAs from the tumor cells revealed a novel platelet-derived growth factor receptor alpha (PDGFRA) mutation, which would exhibit biologic consequences similar to those of the c-kit mutation. The patient underwent a 3-month course of imatinib mesylate as adjuvant chemotherapy because of the possible risk for tumor recurrence. She is now doing well without any evidence of recurrence or metastasis 25 months after the surgery. Only 9 cases of GIST have been reported in children, and a review of those cases revealed GISTs in children would be associated with a better prognosis than in adults and that one third of pediatric GISTs presented with intestinal obstruction in the newborn period.
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PMID:Advanced-stage gastrointestinal stromal tumor treated with imatinib in a 12-year-old girl with a unique mutation of PDGFRA. 1629 Nov 74

We report a rare case in which two tumor entities, a gastrointestinal stromal tumor (GIST) and Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET), with distinct cytogenetic features occurred in a single patient. The patient was a 72-year-old woman. The first tumor was a submucosal gastric tumor and was diagnosed as a low-risk group GIST based on morphological characteristics and the results of an immunohistochemical analysis for c-kit and CD34. Further cytogenetic analysis revealed that this tumor had a point mutation (D842V substitution) in exon 18 of the platelet-derived growth factor receptor alpha gene. The second tumor was found more than 4 years after the appearance of the first tumor. ES/PNET was highly suspected both morphologically and immunohistochemically, and the diagnosis was confirmed by the detection of an EWS rearrangement using a fluorescence in situ hybridization technique. Although the cytogenetic correlations of these two tumors are unclear, accurate histologic recognition is of clinical importance because the treatments for these two tumors differ.
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PMID:Cytogenetic confirmation of a gastrointestinal stromal tumor and ewing sarcoma/primitive neuroectodermal tumor in a single patient. 1633 19

Leydig cells (LCs) are thought to differentiate from spindle-shaped precursor cells that exhibit some aspects of differentiated function, including 3beta-hydroxysteroid dehydrogenase (3betaHSD) activity. The precursor cells ultimately derive from undifferentiated stem LCs (SLCs), which are postulated to be present in testes before the onset of precursor cell differentiation. We searched for cells in the neonatal rat testis with the abilities to: (i) proliferate and expand indefinitely in vitro (self renew); (ii) differentiate (i.e., 3betaHSD and ultimately synthesize testosterone); and (iii) when transplanted into host rat testes, colonize the interstitium and subsequently differentiate in vivo. At 1 week postpartum, spindle-shaped cells were seen in the testicular interstitium that differed from the precursor cells in that they were 3betaHSD-negative, luteinizing hormone (LH) receptor (LHR)-negative, and platelet-derived growth factor receptor alpha (PDGFR alpha)-positive. These cells were purified from the testes of 1-week-old rats. The cells contained proteins known to be involved in LC development, including GATA4, c-kit receptor, and leukemia inhibitory factor receptor. The putative SLCs expanded over the course of 6 months while remaining undifferentiated. When treated in media that contained thyroid hormone, insulin-like growth factor I, and LH, 40% of the putative SLCs came to express 3betaHSD and to synthesize testosterone. When transplanted into host rat testes from which LCs had been eliminated, the putative SLCs colonized the interstitium and subsequently expressed 3betaHSD, demonstrating their ability to differentiate in vivo. We conclude that these cells are likely to be the sought-after SLCs.
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PMID:In search of rat stem Leydig cells: identification, isolation, and lineage-specific development. 1646 41

Imatinib mesylate is a specific inhibitor of the Bcr-Abl protein tyrosine kinase that competes with ATP for its specific binding site in the kinase domain. It has activity against platelet-derived growth factor receptor alpha and beta (PDGFR-alpha and -beta), and c-kit, the receptor for stem cell factor. We have used a standardized ATP-tumor chemosensitivity assay and immunohistochemistry to determine the cytotoxicity of imatinib mesylate in tumor-derived cells from cutaneous and uveal melanoma, and ovarian carcinoma. Imatinib mesylate was tested at concentrations ranging from 2.0 to 0.0625 micromol/l alone and in combination with a cytotoxic drug (cisplatin, doxorubicin, paclitaxel or treosulfan). Imatinib mesylate showed low inhibition (IndexSUM>300) across the range of concentrations tested in this study, with few tumors exhibiting increasing inhibition with increased drug concentration. The median IC90 values for cutaneous and uveal melanoma and ovarian carcinoma were 13.2 micromol/l (4.0-294.3 micromol/l), 12.0 micromol/l (2.0-285.4 micromol/l) and 7.71 micromol/l (6.51-11.02 micromol/l), respectively. Imatinib mesylate potentiated the effect of different cytotoxics in 9% (5/54) of cases and had a negative effect in 13% (7/54) of cases, with no effect in the remainder. No correlation of effect was noted with c-kit, platelet-derived growth factor receptor-alpha or platelet-derived growth factor receptor-beta expression, assessed by immunohistochemistry. The signaling pathways mediated by activation of c-kit or platelet-derived growth factor receptor may act as antiapoptotic survival signals in some cancers and inhibition of these pathways may potentiate the activity of some cytotoxic drugs by inhibiting the survival signal. Growth inhibition, however, may reduce the efficacy of cytotoxic drugs, which tend to target proliferating cells preferentially, and clinical effects are therefore difficult to predict.
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PMID:The effect of imatinib mesylate (Glivec) on human tumor-derived cells. 1691 10

Undifferentiated endometrial sarcoma (UES) is a high-grade sarcoma that lacks specific differentiation. Here, we present a unique case of UES that temporarily responded to imatinib mesylate. A 61-year-old woman presented with a pelvic mass, which rapidly increased in size over the course of 3 months. The mass in the hysterectomy specimen consisted of pleomorphic cells that did not show any endometrial stromal or smooth muscle differentiations; thus, the diagnosis of UES was made. Multiple regional recurrences around the urinary bladder were noted after 5 months, and treatment with imatinib mesylate was started, based on the provisional interpretation of KIT immunoreactivity on a biopsy specimen of the recurrent tumor. Two weeks later, the tumor shrunk significantly, as evaluated by computed tomography. However, they became enlarged under the therapy after 3 months since imatinib was first started. KIT immunohistochemical staining on the previously mentioned biopsy was reviewed thereafter, but it was not convincing. We also investigated for aberrations of c-kit and platelet-derived growth factor receptor alpha by polymerase chain reaction with direct sequencing, but no aberration was observed. Instead, focal but definite immunoreactivity to epidermal growth factor receptor (EGFR) was observed. In addition, EGFR gene amplification was confirmed by fluorescence in situ hybridization. We speculated that imatinib was temporarily effective on the clone with amplified EGFR, and that it became ineffective after this clone was eradicated. The amplified EGFR in UES has not been reported previously, and further studies are necessary to consider the possibility of EGFR-targeted therapy in such sarcomas.
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PMID:KIT-negative undifferentiated endometrial sarcoma with the amplified epidermal growth factor receptor gene showing a temporary response to imatinib mesylate. 1724 Mar 8

KIT or alpha-platelet-derived growth factor receptor (alpha-PDGFR) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors (GIST). Despite excellent responses to imatinib mesylate (IM), patients are relapsing. We developed an IM-resistant GIST cell line (GIST-R) from the IM-sensitive GIST882 cell line (GIST-S) by growing these cells in IM. Gene expression profiling (GEP) of GIST-S, GIST-R cells and two IM resistant GIST patients demonstrated that KIT is downregulated implying a major role in IM resistance. Instead, GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase - AXL - in a 'kinase switch'. Further, the two IM resistant GIST patients express AXL and not c-Kit, seen by immunohistochemistry (IHC). Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to AXL. In GIST-R, AXL is tyrosine phosphorylated and its ligand growth-arrest-specific gene 6 is overexpressed implying autocrine activation. The kinase switch is associated with a morphological change from spindle to epithelioid. Molecular modeling of the kinase domain of mutant c-Kit (V654A) and AXL showed no binding to IM but efficient binding to MP470, a novel c-Kit/AXL kinase inhibitor. MP470 synergizes with docetaxel (taxotere) and is cytotoxic to GIST cells.
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PMID:A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. 1732 67

We report 2 cases of plexiform angiomyxoid myofibroblastic tumor of the stomach, a tumor entity that has not been described previously. The patients were a 50-year-old man (case 1) and a 68-year-old man (case 2). In case 1, the patient presented with acute abdominal pain. The tumor in case 2 was incidentally found at laparoscopic cholecystectomy. Grossly, the tumors were 4.0 cm (case 1) and 4.5 cm (case 2) in their greatest dimension, and they were recognized as submucosal tumors. The tumor caused gastric perforation in case 1. Histologically, the tumors extended from the serosa to the submucosa of the gastric wall, showing a plexiform growth pattern. Bland spindle tumor cells were observed, and they were separated by abundant intercellular myxoid matrix. The stroma was rich in small vessels. Immunohistochemically, the tumor cells were positive for alpha-smooth muscle actin and muscle actin, and negative for KIT, CD34, and S-100 protein. Electron microscopic findings were consistent with the myofibroblastic nature of the tumor cells. No mutations were found in the c-kit and platelet-derived growth factor receptor alpha genes. Although clinical follow-up data were insufficient, the histologic appearances suggested the benign nature of the tumors. However, the tumor in case 1 caused gastric perforation and necessitated an emergency operation.
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PMID:Plexiform angiomyxoid myofibroblastic tumor of the stomach. 1882 97

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract that are believed to originate from a neoplastic transformation of the intestinal pacemaker cells (interstitial cells of Cajal) normally found in the bowel wall or their precursors. Although the microscopic features have been known for a long time, the defining characteristic of GIST is the presence of the cell-surface antigen CD117 (KIT), which is demonstrated by immunohistochemistry. KIT, which is a growth factor transmembrane receptor, is the product of the proto-oncogene c-kit (chromosome 4). Surgical removal remains the only curative treatment for patients with GISTs. Tumor size, mitotic index, anatomic location, tumor rupture and disease-free interval are the classic characteristics used to predict the clinical course of patients who undergo complete gross resection. Most GISTs express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. Imatinib mesylate is a rationally designed, molecularly specific oral anticancer agent that selectively inhibits several protein tyrosine kinases central to the pathogenesis of human cancer and which has demonstrated remarkable clinical efficacy in patients with chronic myeloid leukemia and malignant GISTs. More recently Sunitinib, a new KIT/PDGFRA kinase inhibitor, has been tested in patients with GIST resistant to imatinib, with promising results.
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PMID:Gastrointestinal stromal tumors (GISTs): focus on histopathological diagnosis and biomolecular features. 1759 8

High-resolution melting amplicon analysis (HRMAA) was used to detect c-kit and platelet-derived growth factor receptor alpha (PDGFRA) activating mutations in 96 gastrointestinal stromal tumors (GISTs). HRMAA detected mutations in 87 GISTs (91%). Of the 87 cases, 69 (79%) contained c-kit mutations and 18 (21%), PDGFRA mutations. One c-kit mutation-positive case contained an exon 9 mutation, ins FY at codon 503, that has not been previously described. One PDGFRA mutation-positive case contained mutation D842V del 843, also not previously described. Of 18 PDGFRA mutation-positive cases, 3 (17%) were strongly positive for kit expression as measured by CD117 immunohistochemical analysis. Of 69 c-kit mutation-positive cases, 66 (96%) showed strong kit immunohistochemical expression, but 3 (4%) showed negative to weak CD117 expression. Of 96 cases, 9 (9%) were wild type for c-kit and PDGFRA. Of the wild-type cases, 8 still showed strong immunohistochemical kit expression, whereas 1 showed weak kit expression. GISTs with PDGFRA mutations were found in the stomach, omentum, and peritoneum but not the small intestine. GISTs with c-kit exon 9 mutations were found primarily in the small intestine. HRMAA is a sensitive technique that can be used to rapidly identify c-kit and PDGFRA activating mutations in GISTs.
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PMID:High-resolution melting amplicon analysis as a method to detect c-kit and platelet-derived growth factor receptor alpha activating mutations in gastrointestinal stromal tumors. 1763 56


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