Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Appl Immunohistochem Mol Morphol 2003 Mar
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

Immunohistochemical staining for KIT (CD117) was performed on 144 cases of soft tissue sarcoma and 11 cases of gastrointestinal stromal tumor (GIST). Diffuse global staining in almost all neoplastic cells was a consistent feature of GIST but was also seen in some types of soft tissue sarcoma that resemble GISTs morphologically, such as synovial sarcoma and leiomyosarcoma. This finding is of diagnostic importance because some of these sarcoma types may involve the intestinal wall and simulate primary GIST. Most other positive cases showed focal staining. Although focal positivity may not be a problem in resected specimens, it has the potential to be misleading in biopsy material. Our results are concordant with some reports of CD117 expression in soft tissue tumors, but they differ from those reported by other laboratories. This discrepancy in the literature may be the result of variation in antibodies used or variation in immunohistochemical staining protocol. Regardless of the technical or scientific explanation, an understanding of the difficulties with KIT immunostaining is critical. Not only is KIT positivity used as a prerequisite for the diagnosis of GISTs, but treatment eligibility for STI571 in patients with GIST, and increasingly with other tumors, relies on positive KIT immunostaining.
Appl Immunohistochem Mol Morphol 2003 Mar
PMID:The problem with KIT: clinical implications and practical difficulties with CD117 immunostaining. 1261 Mar 58

Gastrointestinal stromal tumors (GISTs), defined by the presence of constitutively activated KIT, are the most common gastrointestinal mesenchymal malignancies. This observation has been successfully exploited in clinical trials of Gleevec (also known as imatinib mesylate, STI-571) for patients with unresectable and/or metastatic GISTs. The biological mechanisms of Gleevec as well as its downstream molecular effects are generally unknown. We used a DNA microarray-based approach to identify gene expression patterns and signaling pathways that were altered in response to Gleevec in GIST cells. We identified a total of 148 genes or expressed sequence tags (of 10,367) that were differentially regulated; 7 known genes displayed a durable response after treatment. The significantly down-regulated genes were SPRY4A, FZD8, PDE2A, RTP801, FLJ20898, and ARHGEF2. The only up-regulated gene was MAFbx. On a functional level, we demonstrated that imatinib inhibited phosphorylation of KIT, AKT, and extracellular signal-regulated kinase 1/2 without affecting the total level of these proteins and that differential expression of these response genes involved activation of mitogen-activated protein kinase-dependent and -independent pathways. In an attempt to correlate these in vitro findings to clinical data, we examined GIST needle biopsy specimens taken from patients before and after Gleevec administration according to the CSTI571-B2222 Phase II trial and demonstrated that expression levels of the two gene transcripts evaluated correlated well with clinical response. This study emphasizes the potential value of an in vitro cell model to investigate GIST response to imatinib in vivo, for the purpose of identifying important genetic markers of clinical response, mechanisms of drug action, and possible therapeutic targets.
Mol Cancer Ther 2003 Aug
PMID:Response markers and the molecular mechanisms of action of Gleevec in gastrointestinal stromal tumors. 2207 11

Imatinib has tremendously changed the treatment of gastrointestinal stromal tumor (GIST). Research is currently focusing on its optimal use and the mechanisms of resistance that may emerge. A multidisciplinary approach including medical oncologists, surgeons, radiologists, and pathologists is crucial for the optimal management of these patients. Moreover, imatinib treatment in GIST represents an extraordinary model to expand our knowledge on the molecular mechanisms that are basic to the effects of molecularly targeted therapies. This review summarizes the existing knowledge of the imatinib treatment in GIST and describes directions for further development.
Mol Cancer Ther 2005 Mar
PMID:Imatinib and gastrointestinal stromal tumors: Where do we go from here? 1576 59

The authors report a unique case of an intra-abdominal, epithelioid mesenchymal tumor that had an activating mutation of PDGFRA and a strong PDGFRA immunoreactivity but lacked both c-kit mutation and c-kit protein (CD117) expression. IHC study showed that the tumor cells were diffusely and strongly positive for PDGFRA, vimentin, CD34, and Bcl-2 but completely negative for CD117 as well as for muscle, epithelial, endothelial, endocrine, mesothelial, neural, and melanocytic cell markers. Molecular study revealed a mutation at the juxtamembrane domain of exon 12 in PDGFRA gene with GTC to GAC transition at codon 561 (V561D), as shown in the previous mutational studies on gastrointestinal stromal tumor (GIST). This case likely represents an example of GIST with PDGFRA activating mutation and PDGFRA immunoreactivity without CD117 positivity, which has not been documented in the literature. STI 571 (imatinib mesylate [Gleevec]) might be an effective therapy in this case, since Gleevec targets both PDGFRA and c-kit oncoproteins.
Appl Immunohistochem Mol Morphol 2005 Jun
PMID:Epithelioid gastrointestinal stromal tumor with PDGFRA activating mutation and immunoreactivity. 1589 28

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. KIT and PDGFRA activating mutations are the oncogenic mechanisms in most sporadic GISTs. In addition to sporadic occurrences, GISTs are increasingly being recognized in association with neurofibromatosis type 1 (NF1), yet the underlying pathogenic mechanism remains elusive. To gain an insight into the mechanisms underlying GIST formation in NF1 patients, we studied seven GISTs from three NF1 patients with a combination of different techniques: mutation analysis (KIT, PDGFRA and NF1), western blotting, array CGH and ex vivo imatinib response experiments. We demonstrate that (i) the NF1-related GISTs do not have KIT or PDGFRA mutations, (ii) the molecular event underlying GIST development in this patient group is a somatic inactivation of the wild-type NF1 allele in the tumor and (iii) inactivation of neurofibromin is an alternate mechanism to (hyper) activate the MAP-kinase pathway, while the JAK-STAT3 and PI3K-AKT pathways are less activated in NF1-related GIST compared with sporadic GISTs. In conclusion, we report for the first time the molecular pathogenesis of GISTs in NF1 individuals and demonstrate that this type of tumor clearly belongs to the spectrum of clinical symptoms in NF1.
Hum Mol Genet 2006 Mar 15
PMID:Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. 1646 35

The authors studied the concordance among seven pathologists for the histologic diagnosis, interpretation of KIT immunostaining, and determining MIB-1 labeling indices (LI) in 80 adult patients with primary spindle cell tumors, mainly of the gastrointestinal tract, mesentery, retroperitoneum, and pelvis, based on the review of tissue sections using an immunohistochemical panel of antibodies for KIT/CD117, CD34, desmin, smooth muscle actin (SMA), and S-100 protein. Tumors included 30 gastrointestinal stromal tumors (GISTs), 10 leiomyomas, 10 leiomyosarcomas, 10 schwannomas, 10 solitary fibrous tumors, and 10 desmoid-type fibromatoses. The overall concordance with the original diagnosis of each histologic type was 97.9%, the kappa value ranging from 0.95 to 1.00 (mean 0.97), indicating a perfect agreement. The overall interlaboratory concordance with the original interpretation of KIT immunostaining was 91.3%, the kappa value ranging from 0.77 to 0.90 (mean 0.86). The overall interlaboratory concordance with the original interpretation of KIT immunostaining was 91.9%, the kappa value ranging from 0.72 to 0.93 (mean 0.85). The overall concordance for determining MIB-1 LI was 90% with the original evaluation, and the overall kappa value ranged from 0.62 to 0.86 (mean 0.77). These results indicate that it is possible to reliably diagnose GIST and other spindle cell tumors of the gastrointestinal tract with the use of an immunohistochemical panel of antibodies for KIT, CD34, desmin, SMA, and S-100 protein. Although there is clearly unavoidable inter-observer and interlaboratory variability in the interpretation of KIT immunostained sections and interobserver variability in the determination of MIB-1 LI, the concordance between observes is very acceptable, and in most instances such variability can be eliminated by careful reviewing of the hematoxylin and eosin and immunostained sections.
Appl Immunohistochem Mol Morphol 2006 Mar
PMID:Interobserver variability in histologic recognition, interpretation of KIT immunostaining, and determining MIB-1 labeling indices in gastrointestinal stromal tumors and other spindle cell tumors of the gastrointestinal tract. 1654 Jul 30

Gastrointestinal stromal tumors (GISTs) are well-recognized mesenchymal neoplasms of the intestinal tract. A diagnosis of GIST is not always possible using IHC techniques for detection of c-kit. The authors describe a 64-year-old man who presented with an upper abdominal quadrant mass. Histology showed a predominantly epithelioid neoplasm with focal "spindle cell" areas. IHC studies were positive for muscle markers and negative for c-kit. The morphologic and immunophenotypic appearance could be compatible with either a smooth muscle tumor or a GIST. Because of the differences in treatment protocols and prognosis between these two entities, molecular studies to detect c-kit or platelet-derived growth factor receptor (PDGFR) activating mutations were performed. No mutations were found in the c-kit gene, but a mutation was detected in the PDGFR gene. This additional molecular study allowed the authors to formulate the precise diagnosis of a c-kit-negative GIST with strong smooth muscle marker expression.
Appl Immunohistochem Mol Morphol 2006 Mar
PMID:A c-kit-negative gastrointestinal stromal tumor with a platelet-derived growth factor receptor alpha mutation. 1654 Jul 31

STI571 is a specific inhibitor of tyrosine kinases, such as BCR-ABL, platelet-derived growth factor receptor, and c-KIT, and has recently been approved for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors (GISTs). This study demonstrated that STI571 induces cell death in the gastrointestinal stromal tumor cell line, GIST-T1. In these cells, STI571 induced pro-caspase-12 or pro-caspase-7 cleavage and it affected caspase-3 activity and induced the endoplasmic reticulum (ER)-resident chaperone, glucose-regulated protein 78. The STI571-induced cell death was blocked by the protein synthesis inhibitor, cycloheximide. Together, these results suggest that STI571 induces cell death in GIST-T1 cells, at least in part, via the ER stress response.
Int J Mol Med 2006 May
PMID:STI571 (Glivec) induces cell death in the gastrointestinal stromal tumor cell line, GIST-T1, via endoplasmic reticulum stress response. 1659 77

Stature is a highly heritable trait under both polygenic and major gene control. We aimed to identify genetic regions linked to idiopathic short stature (ISS) in childhood, through a whole genome scan in 92 families each with two affected children with ISS, including constitutional delay of growth and puberty and familial short stature. Linkage analysis was performed for ISS, height and bone age retardation. Chromosome 12q11 showed significant evidence of linkage to ISS and height (maximum non-parametric multipoint LOD scores 3.18 and 2.31 at 55-58 cM, between D12S1301 and D12S1048), especially in sister-sister pairs (LOD score of 1.9 for ISS in 22 pairs). These traits were also linked to chromosomes 1q12 and 2q36. The region on chromosome 12q11 had previously shown significant linkage to adult stature in several genome scans and harbors the vitamin D receptor gene, which has been associated with variation in height. A single nucleotide polymorphism (SNP) (rs10735810, FokI), which leads to a functionally relevant alteration at the protein level, showed preferential transmission of the transcriptionally more active G-allele to affected children (P=0.04) and seems to be responsible for the observed linkage (P=0.05, GIST test). Bone age retardation showed moderate linkage to chromosomes 19p11-q11 and 7p14 (LOD scores 1.69 at 57 cM and 1.42 at 50 cM), but there was no clear overlap with linkage regions for stature. In conclusion, we identified significant linkage, which might be due to a functional SNP in the vitamin D receptor (VDR) gene and could be responsible for up to 34% of ISS cases in the population.
Hum Mol Genet 2006 Sep 15
PMID:Evidence for involvement of the vitamin D receptor gene in idiopathic short stature via a genome-wide linkage study and subsequent association studies. 1690 57


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