Browsing by Subject "KIT"

Now showing 1 - 5 of 5
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    Gastrointestinal stromal tumors: Overview of pathologic features, molecular biology, and therapy with imatinib mesylate
    (Murcia : F. Hernández, 2004) Koh, J.S.; Trent, J.; Chen, L.; El-Naggar, A.; Hunt, K.; Pollock, R.; Zhang, W.
    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. These tumors develop at any site but are most commonly reported in the stomach. They originate from the neoplastic transformation of the intestinal pacemaker cell, the interstitial cell of Cajal. GISTs strongly express the receptor tyrosine kinase KIT and have mutations in the KIT gene, most frequently in exon 11 encoding the intracellular juxtamembranous region. Expression of KIT is seen in almost all GISTs, regardless of the site of origin, histologic appearance, or biologic behavior, and is therefore regarded as one of the key diagnostic markers. Distinction from smooth muscle tumors, such as leiomyosarcomas, and other mesenchymal tumors is very important because of prognostic differences and therapeutic strategies. Predicting the biologic behavior of GISTs is often difficult by conventional pathologic examination; tumor size and mitotic rate are the most important prognostic indicators. The prognostic significance of KIT mutations is controversial and thus far has not been clearly linked with biologic behavior. KIT mutations are associated with tumor development, and cytogenetic aberrations are associated with tumor progression. The pathogenesis of GISTs involves a gainof- function mutation in the KIT proto-oncogene, leading to ligand-independent constitutive activation of the KIT receptor. KIT-wild-type GISTs have shown mutually exclusive platelet-derived growth factor receptor (PDGFR) mutation and activation. The use of imatinib mesylate (also known as Gleevec or STI-571) has greatly increased the therapeutic efficacy for this otherwise chemotherapy-resistant tumor. GISTs with very low levels of KIT expression may respond to imatinib mesylate therapy if the receptors are activated by specific mechanisms. KIT-activating mutations fall into two groups: the regulatory type and the enzymatic site type. The regulatory type of mutation is conserved at the imatinib binding site, whereas the enzymatic site mutation has a structurally changed drug-binding site, resulting in drug resistance. Resistance to the drug is the major cause of treatment failure in cancer therapy, emphasizing the need for researchers to understand KIT signaling pathways so as to identify new therapeutic targets. This review summarizes the pathologic features of GISTs, recent advances in understanding their molecular and biologic features, and therapy with imatinib mesylate.
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    Lymphangiogenic VEGF-C and VEGFR-3 expression in genetically characterised gastrointestinal stromal tumours
    (F. Hernández y J.F. Madrid. Murcia: Universidad de Murcia, Departamento de Biología Celular e Histología., 2011) Torres de Oliveira, Antônio Talvane; Reis, Rui M.; Alfonso, Julieta; Martinho, Olga; Matos, Delcio; Lopes Carvalho, André; Buosi Silva, Thiago; Scapulatempo, Cristovam; Sydney Saad, Sarhan; Longatto-Filho, Adhemar
    This study aimed to assess the distribution of VEGF-C and VEGFR-3 expression in gastrointestinal stromal tumours (GISTs), and to analyse the value of lymphatic vessel density (LVD) in a tumour that is believed to preferentially metastasize through blood vessel conduits. A panel of immunohistochemical antibodies was used to evaluate 51 cases of genetically characterised GISTs: VEGF-C, VEGFR-3, D2-40 (for LVD assessment) and CD31 (for blood vessel density – BDV – assessment). The results were correlated with the clinical-pathological data. The large majority of cases (86.2%; 44/51) showed a mutation of the KIT gene, most of them (72.5%; 37/51) revealing mutations in exon 11. VEGFR-3 was predominantly expressed in KIT mutated GISTs (p=0.019). High LVD was correlated with the absence of metastasis (p=0.010) and high BVD showed a positive correlation with the occurrence of metastasis (p=0.049). The strong expression of VEGF-C and VEGFR-3 in GIST’s cells was not correlated with the clinical parameters of aggressiveness, nor with high LVD.
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    Protein expression and gene mutation status of KIT and PDGFRA in renal cell carcinoma
    (F. Hernandez y JuanF. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología., 2012) Terada, Tadashi
    The author investigated protein expression and gene mutations of KIT and PDGFRA in 61 consecutive surgical cases of renal cell carcinoma (RCC). The cases of RCC consisted of 43 clear cell RCC (CCRCC), 9 chromophobe RCC (ChrRCC), or 9 papillary RCC (PaRCC). Normal distribution of KIT and PDGFRA protein was also examined in non-tumorous normal parenchyma (n=10). In normal kidneys, KIT was expressed in distal convoluted tubules and collecting ducts, and PDGFRA in distal and proximal convoluted tubules and collecting ducts. KIT expression was recognized in 9 ChrRCC (100%, 9/9), but not in 43 CCRCC (0%, 0/43) and 9 PaRCC (0%, 0/9). PDGFRA expression was recognized in 7 CCRCC (16%, 7/43) and 2 PaRCC (28%, 2/9), but not in ChrRCC (0%, 0/9). A molecular genetic analysis using PCR-direct sequencing was performed in selected 30 cases (ChrRCC=9, CCRCC=12, PaRCC=9): it revealed no mutations in KIT (exons 9, 11, 13, and 17) or PDGFRA (exons 12 and 18) genes in any cases examined. These results suggest that in normal renal parenchyma KIT is expressed in distal convoluted tubules and collecting ducts, and PDGFRA in proximal and distal convoluted tubules and collecting ducts, that KIT is expressed exclusively in ChrRCC and its incidence is 100%, that KIT-positive ChrRCC was negative for PDGFRA, that PDGFRA is expressed in a small percentage in CCRCC and PaRCC, and that mutations of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) are absent in RCC.
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    Somatic mutation of KIT is rare in small cell lung cancer patients from Northeast China
    (F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Xuan, Hong; Jingshu, Geng; Fang, Yang; Na, Li; Xiaolin, Sheng; Zhaoyang, Yang; Meng, Wang; Gongyan, Chen
    Studies have confirmed that protein overexpression or mutations of KIT are involved in growth and development of a variety of cancers. however, little is known about data of gene mutation and protein expression in small cell lung cancer (SCLC) patients from northeast China.The aim of study is to investigate gene mutation and protein expression in such patients with small cell lung cancer (SCLC) and analyse their clinical significance.The expression of c-Kit protein was analyzed by immunohistochemistry in 77 SCLC samples and 22 normal lung samples. KIT mutations were screened in exons 9, 11, 13, 14, 17 and 18 by DNA direct sequencing.The study showed that positive staining for c-Kit was observed in 28 of 77 SCLC patients . There was no correlations between expression of c-Kit and sex, ages, smoking status, stage. only 1 case was found to have known T801I mutation in exon 17. The median survival (13.9 months) of cases with c-Kit-positive was shorter than that (19.9 months)of cases with c-Kit-negative. The finding revealed that stages was identified as an independent predictive factor for SCLC patients.Our finding reveals that somatic mutation of KIT is rare in SCLC patients from the northeast China and there is no enough evidence comfirming KIT inhibitors for treatment in SCLC.
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    Utility of immunohistochemical investigation of SDHB and molecular genetic analysis of SDH genes in the differential diagnosis of mesenchymal tumors of GIT
    (F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Dubova, M.; Sedivcova, M.; Michal, M.; Kokoskova, B.; Ryska, A.; Smid, D.; Daum, Ondrej
    Loss of expression of beta subunit of succinate dehydrogenase (SDHB) was proved to be present in a subgroup of KIT/PDGFRA wt gastrointestinal stromal tumors (GISTs). To evaluate possible diagnostic utility of SDHB immunohistochemistry in the differential diagnostics of mesenchymal tumors of gastrointestinal tract (GIT), 11 cases of KIT/PDGFRA wt GISTs, 12 gastric schwannomas (GSs), 20 solitary fibrous tumors (SFTs), 4 leiomyomas (LMs), 16 leiomyosarcomas (LMSs), 5 synovial sarcomas (SSs), 3 endometrioid stromal sarcomas (ESSs), and 1 ileal inflammatory myofibroblastic tumor (IMT) were investigated for SDHB immunoexpression together with molecular genetic analysis of genes encoding succinate dehydrogenase (SDH). Three recent cases of KIT/PDGFRA mutant GISTs were used as controls. Among the 11 KIT/PDGFRA wt GISTs, 6 expressed SDHB, 1 of them harboring a sequence change of SDHD. All SDHB-negative cases were SDHB-D wt. In 1 of the control GIST cases molecular genetic analysis revealed an SDHD sequence change in addition to a mutation in KIT exon 11. No SFT was truly SDHBnegative, but in 2 of them the staining was impossible to analyze. Furthermore, 1 SFT carried an SDHB and another 1 SDHD sequence change. All GSs, LMs, LMSs, SSs, ESSs, and IMT were SDHB-positive or nonanalyzable, and SDHB-D wt. Additional factors may play a role in regulating expression of SDHB. Furthermore, SDHB immunohistochemistry alone may be misleading in excluding tumors other than GIST (especially SFT) in the differential diagnosis of KIT/PDGFRA wt mesenchymal tumors of GIT.