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)

Clear cell sarcoma (CCS) of soft tissue is a rare sarcoma with morphologic similarities to malignant melanoma but a distinct genetic background including a chromosomal translocation, t(12;22)(q13;q12), or a resultant EWSR1-ATF1 fusion gene. In addition, the tumors occurring in the gastrointestinal tract may have a variant fusion gene EWSR1-CREB1. This study analyzed the clinicopathologic and molecular genetic features of 33 CCSs of soft tissue. The patients' ages ranged from 13 to 73 years (median, 30 y), and there was a male predominance (20 males, 13 females). The tumors were located in the deep soft tissues of the extremities (N=25) or in the trunk or limb girdles (N=8). The median tumor size was 4 cm (range, 1 to 15 cm). The tumor cells were either spindle or epithelioid, and they were arranged predominantly in a short fascicular (N=19) or a solid sheetlike growth pattern (N=14). Minor histologic variations included the existence of rhabdoid cells (N=8), bizarre pleomorphic cells (N=6), alveolar structures due to loss of cellular cohesion (N=3), and a seminomalike pattern (N=2). Tumor necrosis was evident in 14 tumors, and the mitotic activity ranged from 0 to 43 mitotic figures (MF)/10 high-power fields (HPF) (mean: 4 MF/10 HPF). Immunohistochemically, the tumors were consistently positive for S-100 protein (33/33) and variably or focally for HMB45 (32/33), microphthalmia transcription factor (26/32), Melan A (23/32), CD57 (25/33), bcl-2 (30/32), synaptophysin (14/32), CD56 (7/32), epithelial membrane antigen (12/33), cytokeratin (AE1/AE3) (1/32), CD34 (3/32), c-erbB-2 (10/32), c-kit (5/32), and c-met (5/32). alpha-Smooth muscle actin, desmin, and cytokeratin (CAM5.2) were negative. Reverse transcription-polymerase chain reaction using RNA extracted from formalin-fixed, paraffin-embedded tissues demonstrated transcripts of the EWSR1-ATF1 (31/33) or EWSR1-CREB1 fusion gene (2/33). In 26 cases with available clinical information, local recurrences and metastases developed in 2 and 15 patients, respectively. Ten patients were dead of the disease, and the overall survival rate was 63% at 5 years. However, no clinicopathologic or molecular variables associated with the patients' prognosis were identified. This study confirms that CCS is an aggressive soft tissue tumor with a melanocytic phenotype and wider morphologic variations than had been generally considered. In cases with unusual histologic findings, molecular detection of the EWSR1-ATF1/CREB1 fusion genes provides critical information regarding the diagnosis of the tumor.
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PMID:Clear cell sarcoma of soft tissue: a clinicopathologic, immunohistochemical, and molecular analysis of 33 cases. 1830 Aug 4

Granulocytic sarcoma mimicking a synchronous second primary neoplasm (SPN) constitutes a diagnostic and therapeutic challenge particularly in elderly patients. We report on a 75-year-old female presenting with a Core-binding Factor (CBF) AML of M4eo subtype. The patient also had jaundice, highly elevated bilirubin, lipase, alkaline phosphatase (AP), CA 19-9, and a pancreatic mass highly suspicious of infiltrating pancreatic carcinoma. However, a biopsy demonstrated granulocytic sarcoma. Since the patient had no comorbidities and had been in excellent performance status until the diagnosis of AML, induction chemotherapy was initiated, with subsequent normalization of bilirubin, CA 19-9, lipase and AP. Complete hematologic remission of AML was attained and the pancreatic mass could not be detected anymore. Retrospective analysis of the c-kit protooncogene did not disclose activating mutations of exons 8 or 17. Following one consolidation treatment, the patient remained in excellent health until relapse occurred 7 months later and she succumbed to AML. In conclusion, AML can rarely mimic the clinical picture of pancreatic cancer. The initially good response of this CBF leukemia highlights the principal usefulness of aggressive induction chemotherapy also in older AML patients, if they are carefully selected not only according to biological risk factors such as cytogenetics, but also to "host factors" (good performance status, lack of comorbidities, etc.).
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PMID:Granulocytic sarcoma of Core-binding Factor (CBF) acute myeloid leukemia mimicking pancreatic cancer. 1845 26

Purpose. To study the evolution of concepts concerning gastrointestinal stromal tumours (GISTs) over 30 years.Discussion. GISTs have been, for more than 30 years, the subject of considerable controversy regarding their line of differentiation as well as the prediction of their behaviour. Furthermore, once they spread within the peritoneal cavity, they are extremely hard to control. The recent findings of c-Kit mutations and the immunohistochemical detection of the product of this gene, KIT or CD117, in the mainly non-myogenic subset of this family of tumours, has led to a reappraisal of this group of lesions, which, with some exceptions, is now thought to be derived from the interstitial cells of Cajal, and this has facilitated a clearer definition of their pathological spectrum. In this article, we review chronologically the evolution of the concept of GIST with the gradual application of electron microscopy, immunohistochemistry, DNA ploidy analysis. We discuss the impact of these techniques on the pathological assessment and clinical management of GISTs.
Sarcoma 1998
PMID:Gastrointestinal stromal tumours: an update. 1852 Dec 45

Bone and soft tissue sarcomas are an infrequent and heterogeneous group of mesenchymal tumors, including more than a hundred different entities attending to histological patterns. Sarcomas are quite resistant to conventional chemotherapy (anthracycline and ifosfamide) with the exception of some subtypes, such as Ewing's sarcoma (ES). New drugs with proved efficacy against sarcomas include taxanes, gemcitabine, and ET-743. Preclinical studies have also identified key molecular events leading to the progression and development of sarcomas which are good candidates to targeted therapy. Inhibitors of the tyrosine kinase receptors, such as IGF-1R, c-kit, PDGFR, VEGFR, or the mTOR signaling pathway, proteasome, angiogenesis, and stress response proteins are under clinical evaluation against sarcomas. ES, a tumor characterized by chromosomal translocations that originate gene fusions (EWS-FLI1, EWS-ERG), is an example of a good chemotherapy responder tumor whose survival rate shows a plateau in recent years. Preclinical studies have identified that new targets such as HSP90 are of relevance to ES. On the other hand, recent studies showed the role of cancer stem cells (CSCs) in sarcomas and the relevance of the identification of reliable molecular markers and possible therapeutic targets. New therapeutic approaches could be directed against CSCs. This review describes more recent targeted therapy in sarcomas, with special emphasis on ES and the role of CSCs. We also emphasize the role of high throughput proteomic techniques in identifying new therapeutic targets.
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PMID:Targeting sarcomas: therapeutic targets and their rational. 1901 96

Bone and soft tissue sarcomas are an infrequent group of tumours with a prevalence of 4 in 100,000 people/year. Sarcomas, such as synovial sarcoma, Ewing's sarcoma and osteosarcoma, are more usual in adolescents or in young adults. Neoplasias such as leiomyosarcoma or liposarcoma are more frequent in patients over 55 years. One relevant topic is related to sarcomagenesis elucidation, a key for discovering the early molecular mechanisms involved in the development of sarcomas as well as the identification of reliable molecular markers and possible therapeutic targets. Today, it is known that the cellular context contributes to the phenotype. Analysis of gene expression profiling of human sarcomas revealed tightly clustered groups and could denote the existence of common signalling pathways for each branch. From the molecular point of view, these neoplasias are grouped into two main types: (a) sarcomas showing specific genetic alterations and relatively simple karyotypes, and translocations which originate gene fusions (e.g., EWS-FLI1 in Ewing's sarcoma); or specific genetic mutations (e.g., c-kit in the gastrointestinal stromal tumour), and (b) sarcomas showing unspecific gene alterations and very complex karyotypes, and very numerous gains and losses. This review points out the clinical projection of sarcomagenesis elucidation and knowledge of diverse types of molecular alterations.
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PMID:Molecular pathology of sarcomas. 1914 59

The current standard in local treatment of soft tissue sarcomas has shifted from amputation and similar mutilating resections to more organ- and function-preserving surgery. This was possible through multidisciplinary treatment approaches, particularly those including adjuvant radiation therapy. Adjuvant radiation showed significant improvement in local tumour control after resection with tight margins and in high-risk sarcomas. Unfortunately adjuvant radiation failed to improve overall survival. Perioperative chemotherapies also have not contributed to improvement in the overall prognosis worldwide. Progress may occur when the pathogenesis and molecular profile of specific sarcoma subtypes are better understood, allowing more effective new drugs. One example is the treatment of advanced gastrointestinal stromal tumour with imatinib, a small molecular kinase inhibitor of the c-kit receptor. Presently the most effective measure to improve the prognosis with soft tissue sarcomas is early patient referral to expert centres, where diagnostic workup and therapy decisions are made on a multidisciplinary basis and updated according to the newest guidelines and study results.
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PMID:[Multidisciplinary treatment for adult soft tissue sarcoma]. 1915 92

Gastrointestinal stromal tumors (GISTs) are a rare and heterogeneous group of spindle cell neoplasms that have also been reported outside of gastrointestinal (GI) tract. These tumors are characterized by somatic mutations of c-KIT (CD117), a proto-oncogene that encodes a receptor tyrosine kinase normally expressed in the interstitial cell of Cajal that control the GI smooth muscle peristalsis, and an exquisite sensitivity to the action of the tyrokinase inhibitor imatinib mesylate (STI571; Gleevec). We report two cases of gastrointestinal stromal tumor identified on prostatic biopsies, where a primary prostatic sarcoma was considered in the differential diagnosis. In one of the cases, there was extensive local disease involving prostate, rectum, and pelvic wall, as well as metastatic disease that quickly lead to the patient's death despite aggressive treatment with imatinib mesylate and conventional chemotherapy. In the other case, the tumor was mostly confined to the rectum but also focally extended into the prostate capsule. The patient underwent resection and was alive without disease 18 months after surgery. In both cases, tissue samples from prostate and the rectum showed a malignant spindle cell neoplasm, which was positive for CD117 (c-kit). Given their unique clinical management, gastrointestinal stromal tumors should be considered in the differential diagnosis of spindle cell lesions on prostatic needle biopsies and CD117 should be added to the immunohistochemical panel in the work-up of such lesions to avoid misinterpreting them as primary prostatic neoplasms.
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PMID:Gastrointestinal stromal tumors presenting as a prostatic mass. 1922 92

This review describes the current multidisciplinary management of gastrointestinal stromal tumor (GIST), which is the most common sarcoma of the gastrointestinal tract. Before 2001, surgery was the only effective therapy for GIST. The discovery of the central role of KIT proto-oncogene mutations in the pathogenesis of this tumor, and the development of specific inhibitors of KIT tyrosine kinase (TK) function, has changed the paradigm of treatment for GISTs. Imatinib and sunitinib are TK inhibitors with activity against GISTs. Their major established role in GIST is in the treatment of advanced disease. A growing body of literature and clinical experience support the potential perioperative use of these drugs. The adjuvant use of imatinib is based on retrospective series and limited prospective studies demonstrating that imatinib reduces the risk of recurrence. Ongoing studies are further defining the length of adjuvant therapy, as well as identifying the patients that could achieve the best results. Neoadjuvant treatment often decreases the tumor size, allowing a less morbid surgery, appears to be safe and beneficial for some patients, and therefore deserves further study.
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PMID:Perioperative treatment of gastrointestinal stromal tumors. 1928 24

Gastrointestinal stromal tumor (GIST) is the most common form of sarcoma and can vary in size and clinical outcome from an incidental finding at the time of surgery to life-threatening metastatic disease. Surgery is the standard of care for primary disease, and the oral drug imatinib is the standard of care for metastatic disease. Sunitinib was approved in the United States in early 2006 for GIST refractory to imatinib. The pathology of GIST, surgical options for primary and metastatic disease, and findings leading to the use of imatinib and sunitinib for GIST are reviewed in this manuscript, with attention to the mutation statuses of c-kit and PDGF receptor that lead to imatinib sensitivity or resistance.
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PMID:Gastrointestinal Stromal Tumors (GIST) and Their Management. 1936 Jan 54

Sarcomas are mesenchymal cancers consisting of tumors with various clinical and pathological features. Some of them compel affected individuals to lose important musculoskeletal functions, and some of them are highly malignant and life-threatening. A great amount of genetic information for sarcomas has accumulated during the past two decades, contributing diagnoses and treatments. From the standpoint of molecular genetics, sarcomas are classified into two groups: those with defined genetic alterations and those with various genetic alterations. The genetic alterations in the first group include reciprocal translocations resulting in fusion oncoproteins and oncogenic mutations of defined genes such as those of the c-kit gene in gastrointestinal stromal tumors. The function of fusion proteins includes transcription regulator, signal transducer, chromatic remodeling factor, and growth factor, some of which are suitable targets for the molecular therapy. In tumors belonging to the second group, the number of which is far larger than those of the first group, considerable genetic heterogeneity was found even among tumors with same pathological diagnosis. The disruption of the RB and p53 pathways was frequently found, resulting in the dysregulation of cell cycle and the genomic instability. The application of molecular target therapy for tumors in this group requires novel strategies to overcome cross talk between different signal pathways. Recent evidence from in vitro and in vivo experiments has indicated that the cells of origin of sarcomas are tissue stem cells such as mesenchymal stem cells, and the application of stem cell biology holds the promise of novel treatment options.
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PMID:Molecular genetics of sarcomas: applications to diagnoses and therapy. 1955 93


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