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The protooncogene c-Kit and c-Kit ligand in human disease
Abstract
J Allergy Clin Immunol 1997;100:435-40.
... c-kit is seen in the long arm of chromosome 4 and codes for tyrosine kinase transmembrane receptor, KIT [7][8][9]. When c-KIT binds with its corresponding ligand, it triggers signaling pathways leading to cell division and maturation [10,11]. ...
... Many studies have reported translocation (6,9) in ACCs of head and neck and also of the breast [29][30]. This translocation attaches the MYB gene and the NFIB gene that results in a chimeric transcript. ...
Adenoid cystic carcinoma (ACC) is one of the common aggressive variants of malignant salivary gland tumours. ACC is characterized by local spread, perineural infiltration, and distal metastases. Surgery with or without adjuvant radiotherapy is the treatment of choice. Inadequate molecular insights into signaling that triggers carcinogenesis and invasiveness in ACC together with no representative cell lines available for testing are major blocks to the discovery of more treatment options with better outcomes for this insidious cancer. Common tumour suppressor genes and oncogenes that are known to play essential roles in the pathogenesis of cancers in other organs are seen to be less prevalent in salivary gland cancers. Genes that take part in the carcinogenesis of ACCs are suspected to be unique. More research with goals to identify signaling mechanisms triggering in cancer genesis and spread to improve therapeutic insight is essential. In the short review article, we have tried to summarize all known genetic changes that have been studied and known to be involved in the carcinogenesis of ACC. This would save as a basis for more research to be done in this area with the objective of developing newer targets for treatment.
... Kök hücre faktörü: Kök hücre faktörü mast hücreleri için büyüme, farklılaşma faktörü olarak bilinmektedir ve mast hücre sayısı, fonksiyonuna etki eden en önemli büyüme faktörlerinden biridir. Kök hücre faktörü matür, immatür mast hücrelerinin farklılaşmasını düzenlerken; onların dokuya göçünü, proliferasyonunu ve mast hücre mediatörlerinin salınımını artırtır [4]. Kök hücre faktörü fibroblastlar, endotel hücreleri, keratinositler, kemik iliği stroma hücreleri, üreme hücreleri tarafından üretildiği gösterilmiştir [4]. ...
... Kök hücre faktörü matür, immatür mast hücrelerinin farklılaşmasını düzenlerken; onların dokuya göçünü, proliferasyonunu ve mast hücre mediatörlerinin salınımını artırtır [4]. Kök hücre faktörü fibroblastlar, endotel hücreleri, keratinositler, kemik iliği stroma hücreleri, üreme hücreleri tarafından üretildiği gösterilmiştir [4]. Mast hücrelerinde proliferasyon görülen çeşitli hastalıklarda kök hücre faktörünün salınımının arttığı ve bu hastalıkların patogenezinde önemli rol oynadığı tespit edilmiştir [5,6,7,8,9]. ...
Pterjium, oküler yüzey bozukluğu olup kapak aralığına uyan bölgede bulber konjonktivanın fibro¬vasküler proliferasyonunun korneayı invaze etmesi sonucu oluşan bir patolojidir. Pterjium, cerrahi sonrası nüksün yüksek oranlara ulaştığı bir hastalıktır. Günümüzde nüks oranlarını daha aşağılara çekmek amacıyla birçok yeni cerrahi teknik yanında büyümesini durdurmak için antineoblastikler kullanılmaktadır. Çeşitli büyüme faktörleri ve mediatörlerin bazı neoplazmlar gibi pterjium büyümesi, invazyonu ve nüksünde etkili olduğu bulunmuştur. Kök hücre faktörü ve VEGF gibi büyüme faktörlerinin yanında, histaminde, karbonik anhidraz aktivitesinde, eph B4 sayısında ve nestin salınımında artış bulunurken, IGFBP3 salınımında ise azalma bulunmuştur. Pterjimun büyümesinin durdurulması ve nüksünün önlenmesi için halen çalışmalar yapılmaktadır.
... KIT and PDGFRA belong to the type III transmembrane tyrosine kinase receptor family. [1][2][3][4][5][6][7] This protein family is characterized by a specific molecular structure consisting of an extracellular (EC) domain, a juxtamembrane (JM) domain, and a tyrosine kinase (TK) domain. 1,8 KIT and PDGFRA are activated by their ligands, which are the stem cell factor (SCF) and the PDGF, respectively. ...
... 1,3 SCF/KIT-mediated signaling is critical for normal development and maintenance of different cell types, including hematopoietic stem cells, mast cells, melanocytes, gametocytes, interstitial cells of Cajal, and germ cells. [1][2][3][4][6][7][8][9] Expression of KIT and gain-of-function mutation of the KIT gene have been identified in tumors arising from these cell lineages, such as chronic mye-loid leukemia, human mast cell tumors, GISTs, and germ cell tumors (GCTs). 3,[5][6][7] KIT-TK activity is regulated by the JM domain, which inhibits KIT kinase activity in the absence of the KIT ligand. 1 The gain-of-function mutations in the KIT proto-oncogene result in ligand-independent, constitutive activation of the KIT receptor. ...
Background : KIT and PDGFRA are tyrosine kinase receptors. Stem cell factor/KIT-mediated signaling plays a role in normal spermatogenesis, and the alteration of KIT is important in the pathogenesis of seminomas/dysgerminomas (SD). Methods : To determine the role of expression and mutation of the KIT and PDGFRA genes, we analyzed 16 seminoma cases, 4 spermatocytic seminoma (SS) cases and 8 dysgerminoma cases for KIT and PDGFRA expression and mutation of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) using PCR-SSCP methods. Results : KIT was immunohistochemically positive in all 24 SD cases, and one of four (25%) SS cases. PDGFRA was immunohistochemically evident in 16 of the 24 (66.6%) SD cases, and two of the four (50%) SS cases. KIT expression was significantly reduced in SS compared with seminoma (p=0.0035). Four cases (14.3%) displayed mutation in KIT exon 17 or PDGFRA exon 12. Distant metastasis was present in three cases (10.7%), one of which had a nonsense mutation in KIT. Conclusions : These results indicate that KIT is expressed in the majority of SD cases, but not in most SS cases. However, there was no significant correlation between the clinicopathologic features and mutation or expression of KIT and PDGFRA.
... KIT encodes the tyrosine kinase receptor for kit ligand, also known as stem cell factor encoded by the KITLG gene. The interaction between KIT and KITLG plays an important role in normal cellular functions such as cell proliferation, differentiation, migration, and apoptosis as well as in tumorigenesis [94,95]. Krasagakis et al. noted that overexpression of both c-KIT and KITLG in Merkel cell carcinoma increased cell proliferation and decreased apoptosis [96]. ...
Diarylpentanoid (DAP), an analog that was structurally modified from a naturally occurring curcumin, has shown to enhance anticancer efficacy compared to its parent compound in various cancers. This study aims to determine the cytotoxicity, antiproliferative, and apoptotic activity of diarylpentanoid MS13 on two subtypes of non-small cell lung cancer (NSCLC) cells: squamous cell carcinoma (NCI-H520) and adenocarcinoma (NCI-H23). Gene expression analysis was performed using Nanostring PanCancer Pathways Panel to determine significant signaling pathways and targeted genes in these treated cells. Cytotoxicity screening revealed that MS13 exhibited greater inhibitory effect in NCI-H520 and NCI-H23 cells compared to curcumin. MS13 induced anti-proliferative activity in both cells in a dose- and time-dependent manner. Morphological analysis revealed that a significant number of MS13-treated cells exhibited apoptosis. A significant increase in caspase-3 activity and decrease in Bcl-2 protein concentration was noted in both MS13-treated cells in a time- and dose-dependent manner. A total of 77 and 47 differential expressed genes (DEGs) were regulated in MS13 treated-NCI-H520 and NCI-H23 cells, respectively. Among the DEGs, 22 were mutually expressed in both NCI-H520 and NCI-H23 cells in response to MS13 treatment. The top DEGs modulated by MS13 in NCI-H520—DUSP4, CDKN1A, GADD45G, NGFR, and EPHA2—and NCI-H23 cells—HGF, MET, COL5A2, MCM7, and GNG4—were highly associated with PI3K, cell cycle-apoptosis, and MAPK signaling pathways. In conclusion, MS13 may induce antiproliferation and apoptosis activity in squamous cell carcinoma and adenocarcinoma of NSCLC cells by modulating DEGs associated with PI3K-AKT, cell cycle-apoptosis, and MAPK pathways. Therefore, our present findings could provide an insight into the anticancer activity of MS13 and merits further investigation as a potential anticancer agent for NSCLC cancer therapy.
... It is thought that SCF and c-kit contribute to the MC accumulation and survival in MC-driven disorders. For example, in humans, gain-of-function mutations in c-kit lead to mastocytosis, a disorder characterized by an expansion of MC populations, due to constitutive SCF-independent activation of c-kit [137]. Furthermore, in individuals with various allergic diseases including asthma, allergic rhinitis, and atopic dermatitis, an increased production of SCF [138][139][140][141][142] and elevated MC numbers are commonly seen [143]. ...
Mast cells (MCs) are versatile effector cells of the immune system, characterized by a large content of secretory granules containing a variety of inflammatory mediators. They are implicated in the host protection toward various external insults, but are mostly well known for their detrimental impact on a variety of pathological conditions, including allergic disorders such as asthma and a range of additional disease settings. Based on this, there is currently a large demand for therapeutic regimens that can dampen the detrimental impact of MCs in these respective pathological conditions. This can be accomplished by several strategies, including targeting of individual mediators released by MCs, blockade of receptors for MC-released compounds, inhibition of MC activation, limiting mast cell growth or by inducing mast cell apoptosis. Here, we review the currently available and emerging regimens to interfere with harmful mast cell activities in asthma and other pathological settings and discuss the advantages and limitations of such strategies.
... Bazı çalışmalarda kemik iliği stroma hücreleri, endotel hücreleri, keratinositler ve fibroblastlar tarafından kök hücre faktörü üretildiği gösterilmiştir (12). Kök hücre faktörü matür, immatür mast hücrelerinin farklılaşmasını düzenlerken; onların dokuya göçünü, proliferasyonunu ve mast hücre mediatörlerinin salınımını artırtır (13). Yapılan çalışmalarda pterjiumda konjonktivaya oranla mast hücrelerinin sayısının artmış olduğu, bu durumun kök hücre faktörünü salınımı ile bağlantılı olduğu gösterilmiştir (14). ...
Etiology of Pterygium and Current Treatment Approaches
... Mast cells are derived from hematopoietic progenitor cells (Valent et al., 1991;Galli et al., 1995;Vliagoftis et al., 1997). With rare exceptions, mature mast cells are not identifiable in the blood; instead, the blood contains less differentiated mast cell progenitors. ...
... Mutations in the KIT gene are among the most common events in CBF-AML [13][14][15][16]. There is evidence that certain KIT mutations are associated with a poor prognosis, however, the clinical significance of KIT gene mutations in CBF-AML is not fully understood [15]. ...
Certain subtypes of acute myeloid leukemia occur as a result of the cooperation of several events these are, the formation of fusion genes as a result of chromosomal rearrangements, which leads to the disruption of cell differentiation, and the emergence of mutations that enhance cellular proliferation by activating intracellular signaling pathways. High-throughput sequencing methods reveal characteristic mutation spectra in leukemia associated with different chromosomal disorders. However, the role of mutation events in malignant cell transformation processes remains obscure. We searched for driver mutation events in leukemic cells containing the chimeric CBFB-MYH11 gene, which results from inversion of chromosome 16. Using target enrichment, the coding regions of 84 genes in genomes of 12 children with acute myeloid leukemia with inv(16) were investigated. Somatic mutations have been found in the genes of the proteins of intracellular signaling cascades mediated by receptor tyrosine kinases, such as KIT (41%), NRAS (25%), KRAS (17%), and FLT3 (8.3%). Comparative analysis of samples at the time of diagnosis and during remission was used to assess the role of mutations in the pathogenesis of the disease. Previously undescribed mutations in the KDM6A, NOTCH1, and IDH1 genes, which may be involved in leukemogenesis processes have been identified.
... SCF also suppresses mast cell apoptosis and stimulates mast cell adhesion to extracellular matrix proteins. At the same time, SCF activates mast cells for secretion of mediators such as tumor necrosis factor-α, prostaglandin E, glycosaminoglycans and proteolytic enzymes (Vliagoftis et al., 1997;Huttunen et al., 2002). ...
Background:
Skin hyperpigmentation usually results from an increased number, or activity, of melanocytes. The degree of pigmentation of skin depends on the amount and type of melanin, degree of skin vascularity, presence of carotene, and thickness of the stratum corneum. Common causes of hyperpigmentation include post-inflammatory hyperpigmentation, melasma, solar lentigines, ephelides (freckles), and café-au-lait macules. Some skin tumors can be hyperpigmented as basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and malignant melanoma (MM). Stem cell factor (SCF) is a growth factor and its interaction with its receptor, c-kit, is well known to be critical to the survival of melanocytes.
Methods:
This study was carried out on 60 patients complaining of hyperpigmented skin lesions (20 melasma, 20 solar lentigines, and 20 freckles) and 36 patients with skin tumors (14 BCC, 12 SCC, and 10 MM). Punch skin biopsies were taken from the previous lesions. Immunohistochemical staining of these samples was done using the stem cell factor (SCF).
Results:
There was positive expression of SCF in all cases of melasma, solar lentigines and freckles with significant increase in the intensity of expression in the lesional areas than the non-lesional ones (P=0.004). There was also a statistically significant increase in the expression of SCF in BCC and melanoma tumor cells.
Conclusion:
SCF has a great role in skin hyperpigmented disorders and this can be used as a target for the developing of new antipigmentary lines of treatment by inhibiting SCF. SCF can also be involved in the emergence of some skin tumors.
... C-kit is a proto-oncogene located on the long arm of chromosome 4 that encodes kit (CD117), a membrane-bound glycoprotein of type III receptor tyrosine kinase. Its ligand is the stem cell factor (SCF) [10][11][12][13][14][15][16][17][18][19]. ...
C-kit is a proto-oncogene located on the long arm of chromosome 4. Its product, CD117, is a specific immunohistochemical (IHQ) marker that is associated with response to a potent tyrosine kinase inhibitor therapy with STI-571 (Gleevec®) in chronic myelogenous leukemia and GISTs. In our study, we aimed to evaluate the expression of CD117 in glial tumors as this finding may guide therapeutic approaches for these brain tumors. Ependymomas and oligodendrogliomas, in formalin fixed and paraffin embedded blocks were assayed for CD117 immunoreactivity using anti-c-kit (CD117, DAKO). GISTs were used as positive control. We observed immunoreactivity of CD117 protein in 25.5% of tumors in both histological types. In oligodendrogliomas, there was an association between older age at diagnosis and positivity for CD117 ( P = 0.039). In addition, we observed an association between higher tumor grade (grade III) and positivity for CD117 ( P = 0.007). No clinical association was observed in ependymomas ( P > 0.05). This study encourages further investigations, considering that CD117 may be a possible oncogenic factor in some glial tumors. In this case, tumors that express this marker may eventually benefit from a therapy with selective inhibitors of receptor kinases.
... KIT protein, encoded by proto-oncogene c-kit, is a tyrosine kinase growth factor receptor for stem cell factor (SCF). Generally, KIT is activated by autophosphorylation upon the binding of its ligand SCF [5]; however it is constitutively expressed in a number of cells including mast cells, and hematopoietic stem cells [6]. In humans, KIT is often expressed in angiosarcomas, but it is not detected in most benign vascular tumors, and KIT positivity is more likely related to an immature phenotype [7]. ...
Background:
KIT is a tyrosine kinase growth factor receptor. High expression of KIT has been found in several tumors including canine hemangiosarcoma (HSA). This study investigated the correlation of KIT expression and c-kit sequence mutations in canine HSAs and benign hemangiomas (HAs).
Results:
Immunohistochemistry (IHC) staining confirmed KIT expression in 94.4 % (34/36) of HSAs that was significantly higher than 0 % in HAs (0/16). Sequencing the entire c-kit coding region of HSAs and normal canine cerebellums (NCCs) revealed GNSK-deletion in exon 9. As for exon 9 genotyping by TA-cloning strategy, GNSK-deletion c-kit accounted for 48.6 % (68/140) colonies amplified from12 KIT-positive HSAs, a significantly higher frequency than 14.1 % (9/64) of colonies amplified from six NCCs.
Conclusions:
Due to the distinct expression pattern revealed by IHC, KIT might be used to distinguish benign or malignant vascular endothelial tumors. Moreover, the high incidence of GNSK-deletion c-kit in canine HSAs implicates KIT isoforms as possibly participating in the tumorigenesis of canine HSAs.
... Binding induces receptor homodimerization, transphosphorylation of tyrosine residues, and protein kinase activation (Broudy et al, 1998). Subsequent events lead to gene transcription, cell adhesion and proliferation, including SH2-domain signalling, Jak2 kinase and vav activation, and tyrosine phosphorylation of mitogenactivated protein kinase (MAPK), but the functions of these different pathways have not been clearly established (Vliagoftis et al, 1997;Linnekin et al, 1997). A cascade of molecular events triggering haemopoietic speci®cation, proliferation, migration, as well as lineage commitment and differentiation occur at a number of cellular branchpoints during embryogenesis. ...
... Это обеспечивает направленную миграцию клеток в эпидермис, поскольку меланобласты экспрессируют соответствующие c-kit рецепторы. Мутации в генах, кодирующих steel-фактор или его рецепторы, приводят к образованию больших депигментированных пятен на коже головы и передней поверхности тела (spotting), что свидетельствует о затрудненной миграции предшественников МЦ [64,73]. Регуляторные белки нервной ткани, эндотелины 1-3, которые, как известно, являются и самыми эффективными вазоконстрикторами, в эмбриогенезе способствуют пролиферации, переживанию и миграции меланобластов в дорсолатеральном направлении. ...
This review summarises current data on the origin, structure and functions of skin melanocytes. Methods of melanocyte identification, including the immunohistochemical ones, are presented. Cellular mechanisms of melanosome formation, their transfer from melanocytes to keratinocytes and the problems of melanogenesis control in humans, are discussed.
... Kit expression is extremely important in the development of several cell types, including haematopoietic stem cells, mast cells, germ cells, melanocytes, some epithelial cells and the interstitial cells of Cajal. 1 However, approximately 10-15% of GISTs do not express Kit, 2 within this group, a large subset would have acquired PDGFRA function mutations [3]. Mutations in PDGFRA can represent an alternative mechanism in GIST oncogenesis. ...
Aim of the study: Gastrointestinal stromal tumors (GISTs) may now be considered to encompass mesenchymal tumors that express Kit protein (CD117) or have activating mutations of receptor tyrosine kinase genes (PDGFRA). The purpose of this study is to define clinicopathologic characteristics of gastric GISTs in children. Materials and Methods: We conducted a review of the literature from 1962 and enrolled 85 patients (younger than 16 years of age) with gastric GISTs, including two cases treated in our pediatric surgery unit. All the patients’ clinical data and followup information were reviewed, including age, gender, tumour size and localization, presence of Kit mutation and outcome. Case 1: A 16-year-old girl with a history of weakness and pallor. A computer tomography scan confirmed 4 gastric lesions. The lesion in the fundus was excised and an inferior-middle gastric resection was perfomed. At 3 years follow-up the patient presents a progression of liver metastasis. Case 2: A 13-year-old boy was referred to our pediatric surgery unit because of an ulcerated neoformation of 3-cm-sized located in the gastric antrum. The patient underwent laparotomy gastric wedge resection. At the follow-up of 9 years the patient was disease free. Results: Our results are based on our systematic review of 85 cases. The multifocal disease was identified in 21 children (25%). 10 patients are died, all patients presented liver metastases but only 1 had multiple nodules.
... Thus, more than 30 gain-of-function mutations in the extracellular dimerization domain, the intracellular juxtamembrane domain, and the kinase domain have been identified in the c-Kit receptor. 282,283 The transforming mechanism of these mutations (single or multiple amino acid changes) involves dimer formation resulting in constitutive SCF-independent kinase activation. Upregulation of the kinase activity of c-Kit by somatic mutations has been documented in a number of human malignancies, particularly in gastrointestinal stromal tumours (GISTs) (around 85% to 90% of all diagnosed cases). ...
Michel-Saveur Maira did his PhD in molecular and cellular biology in the laboratory of Dr B Wasylyk (IGBMC, ULP, Strasbourg, France). After a first postdoctoral post in the Research and Development group of Rhone-Poulenc-Rorer (CRVA, Paris, France), he joined the group of Dr B Hemmings at the Friedrich Miescher Institute (FMI, Basel, Switzerland), sponsored by a postdoctoral EMBO fellowship. Since 2001, when he joined Novartis Pharma (NIBR Oncology, Basel, Switzerland) as a laboratory head, his work has mostly focused on targeted therapy drug discovery, most notably against signaling cascade kinases.
... Binding induces receptor homodimerization, transphosphorylation of tyrosine residues, and protein kinase activation (Broudy et al, 1998). Subsequent events lead to gene transcription, cell adhesion and proliferation, including SH2-domain signalling, Jak2 kinase and vav activation, and tyrosine phosphorylation of mitogenactivated protein kinase (MAPK), but the functions of these different pathways have not been clearly established (Vliagoftis et al, 1997;Linnekin et al, 1997). A cascade of molecular events triggering haemopoietic speci®cation, proliferation, migration, as well as lineage commitment and differentiation occur at a number of cellular branchpoints during embryogenesis. ...
Receptor tyrosine kinases (RTKs) mediate cellular responses to the extracellular signals involved in the regulation of cell differentiation and proliferation. Ligand binding initiates a cascade of events, such as receptor dimerization and tyrosine phosphorylation. The c-kit gene encodes an RTK for stem cell factor (SCF), (c-kit ligand, KL), both of which play a critical role in the differentiation and growth of haemopoietic stem cells (HSCs). We investigated the expression of the c-kit and SCF genes and the presence of the corresponding proteins in haemopoietic tissues during human embryogenesis. We have examined c-kit and SCF transcripts levels in human embryonic yolk sac, the AGM region, and liver at different stages of gestation (days 25 to 63), using RT-PCR amplification combined with PhosphorImager quantitative analysis and RNase Protection Assay (RPA). Weak levels of SCF gene expression were observed in the AGM region (days 25 to 34) and high levels were found in the early-stage liver (day 34). The expression of c-kit transcript was observed in all studied tissues, but at various levels. The restricted presence of SCF protein following mRNA expression was demonstrated in embryonic liver CD38+ haemopoietic cells by immunocytochemistry. These observations suggest that the biological function of the c-kit receptor plays an important role in the early stages of human haemopoiesis, and that c-kit/SCF signalling is particularly involved in early human definitive haemopoiesis.
... RTK class III mutations have been linked to a number of haematological malignancies [8]. KIT is a proto-oncogene located on chromosome band 4q11-12, adjacent to the exceptionally analogous platelet-derived growth factor receptor (PDGFR) [9][10][11] and encodes a 145-kDa transmembrane glycoprotein that is a member of the type III receptor tyrosine kinase family [12][13][14]. Stem cell factor promotes KIT dimerization and transphosphorylation when bound, thereby activating downstream signalling pathways integral to proliferation, apoptosis, differentiation and survival of hematopoietic stem cells [14]. ...
... Actually, GISTs can be considered as encompassing mesenchymal tumours that express Kit protein (CD117 in the standardized terminology of leukocyte antigens) or that have activating mutations of receptor tyrosine kinase genes [c-kit or platelet derived growth factor receptor alpha (PDGFRA)]. Kit expression is extremely important in the development of several cell types, including haematopoietic stem cells, mast cells, germ cells, melanocytes, some epithelial cells and the interstitial cells of Cajal [1]. However, approximately 10-15% of GISTs do not express Kit [2]; within this group, a large subset would have acquired PDGFRA function mutations [3]. ...
Aim of the study: Gastrointestinal stromal tumors (GISTs) may now be considered to encompass mesenchymal tumors that express Kit protein (CD117) or have activating mutations of receptor tyrosine kinase genes (PDGFRA). The purpose of this study is to define clinicopathologic characteristics of gastric GISTs in children.
Materials and Methods: We conducted a review of the literature from 1962 and enrolled 85 patients (younger than 16 years of age) with gastric GISTs, including two cases treated in our pediatric surgery unit. All the patients’ clinical data and followup information were reviewed, including age, gender, tumour size and localization, presence of Kit mutation and outcome.
Case 1: A 16-year-old girl with a history of weakness and pallor. A computer tomography scan confirmed 4 gastric lesions. The lesion in the fundus was excised and an inferior-middle gastric resection was perfomed. At 3 years follow-up the patient presents a progression of liver metastasis.
Case 2: A 13-year-old boy was referred to our pediatric surgery unit because of an ulcerated neoformation of 3-cm-sized located in the gastric antrum. The patient underwent laparotomy gastric wedge resection. At the follow-up of 9 years the patient was disease free.
Results: Our results are based on our systematic review of 85 cases. The multifocal disease was identified in 21 children (25%). 10 patients are died, all patients presented liver metastases but only 1 had multiple nodules.
Conclusions: The majority of GISTs occur in girls that suggests a developmentally related sex difference. There are no relationship between multiple locations and worst prognosis. The presence of liver metastases is associated with a shorter survival.
... 28 A study by El-Rifai et al. 37 revealed that benign tumours had a mean of 2.6 cytogenetic abnormalities, malignant primary GISTs had a mean of 7.5 abnormalities, and metastatic GISTs had a mean of 9 abnormalities. There have been no noted chromosomal abnormalities at chromosome 4q, 22 the location of the KIT proto-oncogene, 38 consistent with preservation of functional (or activated) copies of KIT genes. ...
Point to note: In Scotland, the major indications for PET-CT are agreed by a national steering group and the prime recommendations are for lymphoma, non-small cell lung cancer and colorectal cancer. There is the opportunity for patients with other tumour types to have PET-CT scans and these include patients with metastatic GISTs. The Radiological guidance will be reviewed by the Scottish Wide Radiology Steering Group early in 2010. This means the radiological guidance in this document still has to be approved by the national body, but has been included as a guide. The guidelines will be updated to confirm the radiological guidance once it has been approved by the group. The Scottish GIST group developed the original Scottish GIST guidelines in 2003, which were used as a basis for the UK GIST guidelines in 2004. These new guidelines were developed, and brought into line with Scottish practice, by the authors and contributors listed above using the existing UK GIST guidelines (2009) as a starting point. The authors and contributors of the UK GIST guidelines (2009) are shown on the inside cover of this document.
... Está codificado por el protoncogen c-Kit localizado en el cromosoma 4q11-21. Posee sectores intra y extracelulares e intramembranosos, al ligarse el factor del crecimiento con el receptor, se produce dimerización del segundo y activación de la tirosina cinasa en el sector intracelular, produciendo reacciones en cascada que controlan la proliferación, adhesión y diferenciación celular (8) . La expresión del antígeno CD 117 se manifiesta en casi todos los TEGI (90%) (9) y está sujeto a mutaciones en un 50% de los casos, otro de los mecanismos de activación del receptor (10)(11)(12) . ...
We hereby report six patients with inmunohistochemical diagnosis of GIST located in different organs of the gastrointestinal tract and other areas, who were managed at our institution, except one case, starting in 2000 and followed until now in the services of hemato-oncology and surgery. The majority of these patients did not have a clear preoperative diagnosis or presented with high suspicion of a mesenchyunal tumor, complicate by a compressing mass, intestinal obstruction, or bleeding. We describe the most relevant aspects pertinent to diagnosis and pathologic classification, surgical management in the context of current literature reports, with emphasis on the ongoing controversies. Furthermore, we define our policy as a group on the basis of the literature review and the careful analysis of our limited experience.
... RTK class III mutations have been linked to a number of haematological malignancies [8]. KIT is a proto-oncogene located on chromosome band 4q11-12, adjacent to the exceptionally analogous platelet-derived growth factor receptor (PDGFR) [9][10][11] and encodes a 145-kDa transmembrane glycoprotein that is a member of the type III receptor tyrosine kinase family [12][13][14]. Stem cell factor promotes KIT dimerization and transphosphorylation when bound, thereby activating downstream signalling pathways integral to proliferation, apoptosis, differentiation and survival of hematopoietic stem cells [14]. ...
The KIT gene is a receptor tyrosine kinase class III expressed by early hematopoietic progenitor cells and plays a significant role in hematopoietic stem cell proliferation, differentiation and survival which is considered to be a remarkable feature in the course of growth of acute myeloid leukaemia (AML). Owing to insufficient study of mutations in the KIT gene, the diagnosis and rate of recurrence of these mutations with divergent subtypes in AML cases in India is of concern. In order to find out the frequency of mutations of KIT gene exon 8 in 109 AML cases, we have performed polymerase chain reaction–single-strand conformation polymorphism (PCR–SSCP) followed by DNA sequencing and have identified 24 mutations in exon 8 in 13 cases, including deletions at codon 418 (n = 3), 419 (n = 11) and 420 (n = 5) as well as point mutations at codon 417 (n = 1) and 421 (n = 4). In eleven AML cases, exon 8 deletion and point mutations involved the loss at codon Asp419 immoderately conserved cross species placed in the receptor extracellular domain. Frequency elevation of the KIT proto-oncogene exon 8 deletion and point mutations in AML cases allude a crucial function for this region of the receptor extracellular domain. Thus, we report the incidence of acquired mutations in exon 8, with consistent loss at codon Asp419, in 10.09 % of AML cases in a selected Indian population.
... Although various chemotherapy regimens have been tried, none has proved to be effective in the treatment of ACC (Jeng et al., 2000). The transmembrane tyrosine kinase receptor c-kit (CD117) is a 145-to 165 Kd proto-oncogene that structurally belongs to a family of receptors that include those for colony-stimulating factor-1 (CSF-1) and platelet derived growth factor (PDGF) (Vliagoftis et al., 1997; Jeng et al., 2000 ). After binding to the ligand (stem cell factor), dimerization, and phosphorylation , the receptor tyrosine kinase (c-kit) subsequently activates a signaling cascade that regulates cell growth and development of multiple hematopoietic cell lineages (Fletcher, 2004). ...
Adenoid cystic carcinoma (ACC) of the salivary gland is characterized by a prolonged but inevitably unfavorable clinical course. Recent studies have suggested that the transmembrane tyrosine kinase receptor, c-kit proto-oncogene is involved in ACC pathogenesis. CD43 is a sialoglycoprotein that is typically expressed by hematopoietic cells and their derivative neoplasms, although positivity in epithelial tumors has only been recognized recently.
The aim of this study was to evaluate c-kit and CD43 immunoreactivity in ACCs and to compare the extent of their expression in various histologically defined subgroups of ACC, and their probable involvement in ACC pathogenesis.
Formalin-fixed paraffin-embedded sections from 35 ACCs were immunostained for c-kit and CD43 using monoclonal antibodies.
Cytoplasmic and membranous c-kit immunoreactivity was detected in 25/35 ACCs (71.4%) with strong immunostaining observed in solid pattern of ACC. Cytoplasmic and membranous CD43 immunoreactivity was detected in 18/35 (51.4%) of ACCs with strong immunostaining seen in the cribriform pattern.
These results suggested that c-kit could be used as a prognostic marker for ACC and specific c-kit tyrosine kinase inhibitors such as imatinib, might be used in future therapeutic approaches against subgroups of ACC. CD43 appears to be preferentially expressed in salivary gland ACCs. Its expression decreased with cellular dedifferentiation and there was an inverse relationship between immunoexpression of c-kit and CD43 among ACC of salivary gland.
KIT ligand and its associated receptor KIT serve as a master regulatory system for both melanocytes and mast cells controlling survival, migration, proliferation and activation. Blockade of this pathway results in cell depletion, while overactivation leads to mastocytosis or melanoma. Expression defects are associated with pigmentary and mast cell disorders. KIT ligand regulation is complex but efficient targeting of this system would be of significant benefit to those suffering from melanocytic or mast cell disorders. Herein, we review the known associations of this pathway with cutaneous diseases and the regulators of this system both in skin and in the more well‐studied germ cell system. Exogenous agents modulating this pathway will also be presented. Ultimately, we will review potential therapeutic opportunities to help our patients with melanocytic and mast cell disease processes potentially including vitiligo, hair greying, melasma, urticaria, mastocytosis and melanoma.
The Mast/Stem cell growth factor receptor Kit (c-Kit), a Proto-oncogene c-Kit, is a tyrosine-protein kinase involved in cell differentiation, proliferation, migration, and survival. Its role in developing certain cancers, particularly gastrointestinal stromal tumors (GISTs) and acute myeloid leukemia (AML), makes it an attractive therapeutic target. Several small molecule inhibitors targeting c-Kit have been developed and approved for clinical use. Recent studies have focused on identifying and optimizing natural compounds as c-Kit inhibitors employing virtual screening. Still, drug resistance, off-target side effects, and variability in patient response remain significant challenges. From this perspective, phytochemicals could be an important resource for discovering novel c-Kit inhibitors with less toxicity, improved efficacy, and high specificity. This study aimed to uncover possible c-Kit inhibitors by utilizing a structure-based virtual screening of active phytoconstituents from Indian medicinal plants. Through the screening stages, two promising candidates, Anilinonaphthalene and Licoflavonol, were chosen based on their drug-like features and ability to bind to c-Kit. These chosen candidates were subjected to all-atom molecular dynamics (MD) simulations to evaluate their stability and interaction with c-Kit. The selected compounds Anilinonaphthalene from Daucus carota and Licoflavonol from Glycyrrhiza glabra showed their potential to act as selective binding partners of c-Kit. Our results suggest that the identified phytoconstituents could serve as a starting point to develop novel c-Kit inhibitors for developing new and effective therapies against multiple cancers, including GISTs and AML. The use of virtual screening and MD simulations provides a rational approach to discovering potential drug candidates from natural sources.Communicated by Ramaswamy H. Sarma.
Over the past decade, immunotherapy has emerged as one of the most promising approaches to cancer treatment. The use of immune checkpoint inhibitors has resulted in impressive and durable clinical responses in the treatment of various cancers. Additionally, immunotherapy utilizing chimeric antigen receptor (CAR)-engineered T cells has produced robust responses in blood cancers, and T cell receptor (TCR)-engineered T cells are showing promising results in the treatment of solid cancers. Despite these noteworthy advancements in cancer immunotherapy, numerous challenges remain. Some patient populations are unresponsive to immune checkpoint inhibitor therapy, and CAR T cell therapy has yet to show efficacy against solid cancers. In this review, we first discuss the significant role that T cells play in the body’s defense against cancer. We then delve into the mechanisms behind the current challenges facing immunotherapy, starting with T cell exhaustion due to immune checkpoint upregulation and changes in the transcriptional and epigenetic landscapes of dysfunctional T cells. We then discuss cancer-cell-intrinsic characteristics, including molecular alterations in cancer cells and the immunosuppressive nature of the tumor microenvironment (TME), which collectively facilitate tumor cell proliferation, survival, metastasis, and immune evasion. Finally, we examine recent advancements in cancer immunotherapy, with a specific emphasis on T-cell-based treatments.
A number of studies have reported frequent incidence of c-kit gene mutations in association with core binding factor acute myeloid leukemia (CBF-AML). These genetic changes have become important prognostic predictors in patients with abnormal karyotype. Aim of this study was the detection of nucleotide alterations in newly diagnosed acute myeloid leukemia patients for three exons of c-kit gene, including cytogenetically normal patients. Thirty-one de novo AML patients were screened for any possible variations in exon 8, 11 and 17 sequences of c-kit proto-oncogene leading to amino acid substitutions or frame shift. Sanger sequencing method was employed followed by sequence analysis. Mutation data was then correlated with clinical and hematological parameters of patients and prognostic significance of genetic changes was assessed as well. The computational tools were then used to further understand the extent of damage caused by these mutations to c-kit protein. Fifteen (48.4%) mutant patients were observed with single, double or multiple mutations in one, two or all three exons studied. The analysis revealed eight new alterations which were not reported previously. Significant variation among mutant and non-mutant group of patients was observed with respect to FAB subtypes (x² = 12.524, p = 0.029), Spleen size (x² = 4.288, p = 0.038) and Red blood cell count (x² = 8.447, p = 0.007). The survival analysis indicates poor overall and event free survival outcomes in mutant individuals. Furthermore, the in silico analysis suggests that changes in nucleotide sequences can possibly damage the protein structure and effect it’s function. This study emphasizes the need to consider screening of c-kit gene alterations not only in CBF-AML but in cytogenetically normal AML patients as well. In current investigation the effect of mutation Arg420Gly on structure and function of c-kit protein was investigated, as this was the most observed substitution in present cohort. Various bioinformatics tools and techniques were employed, which determined that Arg420Gly is possibly non-pathogenic mutation.
Biomarkers in Medicine is a comprehensive guide to understanding the current and future status of biomarkers. The book features 27 chapters focusing on disease biomarkers for diseases such as cancer, neurodegenerative diseases, cardiac diseases, metabolic conditions and much more.
This book supplies readers with the unique insight of experts in multiple specialties in medicine and life sciences who have extensive experience in diagnostics and clinical laboratories. The book includes case studies and practical examples from different classes of biomarkers on different platforms, including new data for biomarkers in different therapeutic indications. In addition to presenting biomarker information, each chapter covers the relevant pathology and also emphasizes on preclinical and clinical manifestation of the disease process.
Clinicians managing patients or clinical trials, clinical researchers, clinical laboratories, diagnostic companies, regulatory agencies, medical school graduate students, academic students, and the general public involved in healthcare delivery will all benefit from information presented in this book.
Most children with tumors will require one or more surgical interventions as part of the care and treatment, including making a diagnosis, obtaining adequate venous access, performing a surgical resection for solid tumors (with staging and reconstruction), performing procedures for cancer prevention and its late effects, and managing complications of treatment; all with the goal of improving survival and quality of life. It is important for surgeons to adhere to sound pediatric surgical oncology principles, as they are closely associated with improved local control and survival. Unfortunately, there is a significant disparity in survival rates in low and middle income countries, when compared to those from high income countries.
The International Society of Paediatric Surgical Oncology (IPSO) is the leading organization that deals with pediatric surgical oncology worldwide. This organization allows experts in the field from around the globe to gather and address the surgical needs of children with cancer. IPSO has been invited to contribute surgical guidance as part of the World Health Organization Initiative for Childhood Cancer. One of our goals is to provide surgical guidance for different scenarios, including those experienced in High- (HICs) and Low- and Middle-Income Countries (LMICs). With this in mind, the following guidelines have been developed by authors from both HICs and LMICs. These have been further validated by experts with the aim of providing evidence-based information for surgeons who care for children with cancer.
We hope that this initiative will benefit children worldwide in the best way possible.
Simone Abib, IPSO President
Justin T Gerstle, IPSO Education Committee Chair
Chan Hon Chui, IPSO Secretary
Certain subtypes of acute myeloid leukemia occur as a result of the cooperation of several events these are, the formation of fusion genes as a result of chromosomal rearrangements, which leads to the disruption of cell differentiation, and the emergence of mutations that enhance cellular proliferation by activating intracellular signaling pathways. High-throughput sequencing methods reveal characteristic mutation spectra in leukemia associated with different chromosomal disorders. However, the role of mutation events in malignant cell transformation processes remains obscure. We searched for driver mutation events in leukemic cells containing the chimeric CBFB-MYH11 gene, which results from inversion of chromosome 16. Using target enrichment, the coding regions of 84 genes in genomes of 12 children with acute myeloid leukemia with inv(16) were investigated. Somatic mutations have been found in the genes of the proteins of intracellular signaling cascades mediated by receptor tyrosine kinases, such as KIT (41%), NRAS (25%), KRAS (17%), and FLT3 (8.3%). Comparative analysis of samples at the time of diagnosis and during remission was used to assess the role of mutations in the pathogenesis of the disease. Previously undescribed mutations in the KDM6A, NOTCH1, and IDH1 genes, which may be involved in leukemogenesis processes have been identified.
The functional inhibition of mast cells, which serve as a key effector cells in allergic reactions may be a specific target for treating immunoglobulin (Ig)E-mediated allergic reactions, which occur in various allergic diseases including anaphylaxis, asthma, and atopic dermatitis. In this study, we demonstrated the effects of dabrafenib, a therapeutic agent used to treat metastatic melanoma, with a focus on mast cell activation and local cutaneous anaphylaxis. In two types of mast cells (RBL-2H3 and mouse bone marrow-derived mast cells), dabrafenib (0.01, 0.1, 1 μM) pretreatment significantly decreased IgE-induced degranulation, intracellular calcium influx, and the activity of intracellular signaling molecules, such as Lyn, Syk, Akt, and PLCγ. Dabrafenib ameliorated mRNA and protein expression levels of interleukin-4 and tumor necrosis factor-α by the reduction of nuclear localization of nuclear factor-κB and nuclear factor of activated T-cells. In passive cutaneous anaphylaxis, oral administration of dabrafenib (0.1, 1, 10 mg/kg) reduced local pigmentation and ear thickness in a dose-dependent manner. Taken together, these results suggest that dabrafenib is a therapeutic drug candidate that controls IgE-mediated allergic inflammatory diseases through suppression of mast cell activity.
Mastocytosis is defined by abnormal accumulations of mast cells in various tissue sites. The clinical features of this multifaceted disorder originate from mast cell infiltration leading to local and systemic effects induced by numerous pharmacological mediators. As mastocytosis is an unusual disorder and presents a multiplicity of symptoms, it is an often overlooked consideration in a differential diagnosis that includes not only chronic diarrhoea, urticaria, syncope and peptic ulceration but also various haematological neoplasms. Diagnosis of mastocytosis can be confirmed only by the pathologist who should use a combined immunohistochemical and molecular approach. Recognition and subtyping of its rare, life‐threatening high‐grade disease variants including aggressive systemic mastocytosis and mast cell leukaemia is based on the thorough investigation of tissue samples (usually bone marrow) but also smear preparations of blood and bone marrow.
Key Concepts
Mastocytosis is an unusual haematopoietic disorder derived from transformed bone marrow progenitor cells.
Clinically and histologically, mastocytosis presents an extremely broad spectrum of subvariants ranging from a benign, sometimes even regressive, cutaneous disease to the progressively fatal mast cell leukaemia.
Mastocytosis is a histological diagnosis established by the pathologist and cannot be confirmed by clinical findings alone.
Most patients with systemic mastocytosis carry the activating point mutation KIT ‐D816V.
The presence of KIT ‐D816V enables targeting therapy using some of the recently developed tyrosine kinase inhibitors.
Although stated in the recent WHO classification system on haematopoietic neoplasms, mastocytosis should not be grouped among myeloproliferative neoplasms.
Mastocytosis rather should be considered as a distinct group of disorders among haematological tumours/neoplasms.
Mastocytosis must be separated from a variety of reactive (mast cell activation syndrome) and neoplastic (basophilic and myelomastocytic leukaemias) disease states.
In more than 80% of patients with advanced systemic mastocytosis (aggressive and leukaemic SM and SM‐AHNMD) mutations other than KIT‐D816V are detected.
Purpose of review:
Testicular germ cell tumors (TGCTs) are a model for curable cancer because of exquisite chemosensitivity and incorporation of multimodal therapy. Nevertheless, our ability to predict metastases in early-stage disease and responders to chemotherapy in advanced disease is limited. Treatment options for cisplatin-resistant disease are sparse. A further understanding of TGCT biology may allow for more precise patient counseling and identify novel therapies in patients with cisplatin-resistant disease.
Recent findings:
Adult TGCTs are characterized by frequent chromosomal anomalies and low rates of somatic mutations. Large-scale integrated molecular analysis of early-stage TGCT patients is actively underway. In addition to ubiquitous gain of isochromosome 12p, current molecular studies have confirmed mutations of previously described genes (i.e., KIT and KRAS) and described novel mutations. Analysis of cisplatin-resistant cases has identified high rates of alterations within the TP53-MDM2 axis and a high proportion of patients with potentially actionable targets, including TP53-MDM2, PI3 kinase, and MAPK signaling pathway alterations. The role of epigenetics in TGCT development and prognosis is also being further characterized.
Summary:
Further molecular characterization of TGCT may allow for avoidance of unnecessary treatment in patients with early-stage disease and also provide new treatment options in patients with cisplatin-resistant disease.
Human genomic DNA from 90 cases of acute myeloid leukemia (AML) were screened for mutations in the c-kit gene. C-kit is a receptor tyrosine kinase class III that is expressed by early hematopoietic progenitor cells and plays crucial role in hematopoietic stem cell proliferation, differentiation and survival. exon 8 and 17 are the frequent sites of mutations in the leukemia cases. To determine the spectrum of mutations at exon 8 and 17 of c-kit gene in 90 acute myeloid leukemia AML cases, we have done Polymerase Chain Reaction (PCR) Single-strand conformational polymorphism (SSCP) followed by DNA sequencing. The c-kit mutation frequencies in exon 8 were 25.55% (23/90) and in exon 17 were 34.44% (31/90) in AML cases. We have detected two contrary deletions Tyr 418del and Asp 419del in exon 8 in 23 cases and three point mutations that is Asp816Val, Asp820Gly and Asn822Lys in exon 17, in 31 cases; respectively. Each and every mutations detected in our study are located in region of the receptor's extracellular domain and intracellular domain of second catalytic region. It gives the impression that incidence of mutation at exon 8 and 17 is elevated and possibly involved in clinical pathogenesis of AML and utilizable tool as the molecular prognostic marker.
The overexpression of c-Kit in chromophobe renal cell carcinoma (ChRCC) has been described by comparative gene expression analyses and has been proposed as a possible specific hallmark of this neoplasm. The aim of our study was to establish its immunohistochemical expression in a large series of ChRCC and to compare it with other renal neoplasms. In our study, immunohistochemical characterization of KIT was performed in 87 renal neoplasms including 25 cases of ChRCC, 13 cases of renal oncocytoma, and 39 renal cell carcinomas (21 cases of conventional RCC [CRCC], 8 cases of CRCC with granular cell differentiation, and 10 cases of papillary RCC [PRCC]). Eighty-eight percent ChRCC and 71% oncocytomas showed immunohistochemical expression of KIT, while the other types of RCC studied were all negative. The meaning of immunohistochemical expression of KIT in ChRCC and oncocytomas is still unknown, but its immunohistochemical staining appears to be useful in distinguishing ChRCC from PRCC, CRCC, and its granular cell variant. Moreover, our findings support current models that consider that there is a histopathogenic relationship between oncocytoma and ChRCC. Finally, it should be determined whether KIT plays a role in the tumorigenesis of ChRCC and oncocytoma and whether targeted therapy with STI-571, an inhibitor of KIT, could be effective in exceptional cases of ChRCC with metastatic extension or recurrence.
Gastrointestinal stromal tumor or smooth muscle tumor (GIST) is the designation for a major subset of gastrointestinal mesenchymal tumors that histologically, immunohistochemically, and genetically differ from typical leiomyomas, leiomyosarcomas, and schwannomas. Because GISTs, like the interstitial cells of Cajal, the gastrointestinal pacemaker cells, express CD117 (c-kit protein), the origin of GISTs from the interstitial cells of Cajal has been recently proposed. Comparison of GISTs primary in the omentum and mesentery to GISTs primary in the tubular gastrointestinal tract is of particular diagnostic and histogenetic interest in view of the possible similarity of these tumors with the GIST group. In this study, we analyzed 14 omental and 12 mesenteric primary mesenchymal tumors representing smooth muscle tumors or GISTs. These tumors were phenotypically compared with gastric and small intestinal GISTs, leiomyomas of the esophagus, and leiomyosarcomas of the retroperitoneum. Most (13 of 14) omental and mesenteric (10 of 12) tumors showed histologic features similar to GISTs with elongated spindle cells or epithelioid cells with high cellularity; most of these tumors showed low mitotic activity. Omental and mesenteric GISTs were typically positive for CD117 and less consistently for CD34. They often showed α-smooth muscle actin reactivity but were virtually negative for desmin and S-100 protein. One omental and two mesenteric tumors showed features of leiomyosarcoma with ovoid, less elongated nuclei, cytoplasmic eosinophilia; all these tumors had significant mitotic activity. These tumors were positive for α-smooth muscle actin and two of them for desmin, but all were negative for CD34 and CD117, similar to retroperitoneal leiomyosarcomas. Tumor-related mortality occurred in the group of mesenteric GISTs, but not in the group of omental GISTs. In contrast, all three patients with a true leiomyosarcoma of the omentum or mesentery had documented liver metastases or died of tumor. In summary, we show that tumors phenotypically identical with GISTs occur as primary tumors in the omentum and mesentery. The occurrence of CD117-positive tumors outside the gastrointestinal tract militates against an origin of these tumors exclusively from the interstitial cells of Cajal.
Although rare elsewhere in the gastrointestinal tract, leiomyomas (LMs) are the most common esophageal mesenchymal neoplasms. In contrast, gastrointestinal stromal tumors (GISTs) predominate in the stomach and intestines but have not been documented in the esophagus. This study was undertaken to determine the clinicopathologic features and frequency of esophageal GISTs compared with LMs and leiomyosarcomas (LMSs) of the esophagus. A total of 68 stromal/smooth muscle tumors from the Armed Forces Institute of Pathology and the Haartman Institute of University of Helsinki were reclassified by current histologic and immunohistochemical criteria. There were 17 GISTs, 48 LMs, and three LMSs. The esophageal GISTs occurred in 12 men and five women with a median age of 63 years (range, 49–75 years). All tumors were from the lowest third of the esophagus, and the most common complaint was dysphagia, whereas two tumors were detected incidentally. Histologically the tumors had an overall basophilic appearance and showed combinations of solid, myxoid, and perivascular collarlike patterns with a spindle cell histology in 13 patients and epithelioid histology in four patients. All tumors were positive for CD117 and for CD34, whereas two patients were also positive for α-smooth muscle actin (SMA) and three patients were positive for desmin. One patient showed a unique immunophenotype with coexpression of CD117, CD34, SMA, and desmin. Nine patients died of disease, including all who had a tumor larger than 10 cm, and also one patient whose tumor showed five mitoses per 50 high-power fields. In comparison, esophageal LMs (n = 48) occurred in a younger population (median age, 35 years) but, similar to the GIST group, men predominated (67%). All LMs were clinically indolent tumors with no tumor-related mortality. The LMs showed eosinophilic cytoplasm, and were positive for desmin and SMA, and negative for CD117 and CD34. All three LMSs were large high-grade tumors that showed muscle cell markers but no CD117. All patients died of disease. Esophageal GISTs showed mutations in exon 11 of c-kit as described previously in gastric and intestinal GISTs. The separation of GISTs from esophageal LMs is important diagnostically because the former group has a high risk of malignant behavior. Leiomyomas (LMs), tumors that show histologic resemblance to normal smooth muscle cells, are the most common mesenchymal tumors of the esophagus. However, they are rare elsewhere in the gastrointestinal (GI) tract. 1,19,36 By contrast, most GI mesenchymal tumors belong to the group of specific gastrointestinal stromal tumors (GISTs). These are cellular spindle or epithelioid tumors that show rudimentary if any smooth muscle differentiation, 18,19 and correspond largely to the previous designations of cellular LM, 2 leiomyoblastoma, and leiomyosarcoma (LMS). 3 Although the typical LMs are positive for actin and desmin, and negative for CD34, the stromal tumors are usually positive for CD34, almost uniformly negative for desmin, and are negative for smooth muscle actin (SMA) in the majority of patients. 21,22,24,37 By electron microscopy, the stromal tumors are heterogeneous and may show smooth muscle or autonomous nerve system-like differentiation or both, or no differentiation at all in some patients. 6 Perhaps the best defining feature for the stromal tumors is their expression of KIT-protein (CD117), which is not present in LMs. 9,11,31,34 Also, activating mutations have been found in the juxtamembrane domain of the c-kit gene in a subset of GISTs. 9,12,14,25–27 Additional differences between esophageal LMs and GISTs have been shown in deoxyribonucleic acid (DNA) copy number changes. 30 The current Armed Forces Institute of Pathology (AFIP) fascicle of tumors of esophagus and stomach states that “it is not clear whether there is a group of unique malignant stromal tumors of the esophagus as there is in the stomach.”16,p.151 During recent years we have encountered several examples of esophageal stromal tumors that corresponded histologically to GISTs seen in the stomach and small intestine. Such esophageal stromal tumors have not been generally recognized and have not been separated from smooth muscle tumors, and their pathologic features and clinical behavior have therefore remained uncharacterized. In this study, we describe CD117-and CD34-positive esophageal stromal tumors as a minority of esophageal mesenchymal neoplasms, and compare them with typical LMs and LMSs. We also demonstrate that the esophageal stromal tumors show c-kit gene mutations as documented previously in gastric and intestinal GISTs, thereby being fully comparable with the GISTs in their main locations. 8,14
Gastrointestinal stromal tumours (GISTs) comprise the largest subset of mesenchymal tumours of the digestive tract. These tumours have been the subject of considerable debate in the literature regarding their histogenesis, criteria for diagnosis, prognostic features and biological behaviour.
The majority of GISTs express CD117 immunostaining and show various degrees of differentiation towards the phenotype of interstitial cell of Cajal.
Clinically and histologically, GISTs represent a spectrum that includes benign and malignant variants. The prediction of clinical behaviour is best achieved by evaluation of multiple parameters including clinical, morphological and cytogenetic features.
The recognition of the central role played by activating mutations of c-kit and platelet derived growth factor receptor alpha in the pathogenesis of GISTs and the introduction of STI-571, a receptor tyrosine kinase inhibitor that has proved extremely effective in the treatment of GISTs, have not only have focused attention on these tumours but also made it necessary to accurately define these tumours and separate them from other mesenchymal lesions. This review discusses the definition, histogenesis, epidemiology, clinical presentation, morphological and immunohistochemical features and the differential diagnosis of GISTs and addresses predictors of malignancy and management of GISTs.
Abstract KIT/KITLG signaling system is crucial for spermatogenesis, which suggests that KIT and KITLG genes may be involved in spermatogenesis impairment and male infertility. To explore the possible association of KIT and KITLG genes with male infertility having spermatogenesis impairment, polymorphism distributions of SNP rs3819392 in KIT gene as well as rs995030 and rs4474514 in KITLG gene were investigated in 372 patients with idiopathic azoospermia or oligospermia and 205 fertile controls. As a result, the significant differences in polymorphism distributions of SNP rs3819392 in KIT gene and rs4474514 in KITLG gene were observed between the patients with oligospermia and controls. The frequencies of allele G (94.2% versus 90.0% p = 0.022) and genotype GG (89.2% versus 82.0% p = 0.042) in patients with oligospermia were significantly higher than those in controls at rs3819392 locus in KIT gene. In addition, the genotype CC of rs4474514 in KITLG (8.2% versus 3.4%, p = 0.034) also significantly increased in oligospermic patients in comparison to controls. These findings indicated that SNP rs3819392 in KIT gene and rs4474514 in KITLG gene may be associated with oligospermia, suggesting that polymorphism of KIT and KITLG genes may play a role in oligospermia.
Gastrointestinal stromal tumors (GIS) are a heterogeneous group of tumors that express CD 117 molecule in their sur face. They may behave as benign tumors or be highly aggressive. A better survival ofpatients with these tumors has been achieved using the new molecular therapies such as imatinib mesylate, sunitinib and others. This review analyzes the prognostic factors of these tumors, their clinical features and the criteria for malignant behavior. The valué of therapeutic alternatives such as radiotherapy chemotherapy and the new molecular therapies are also discussed
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs express KIT and show gain-of-function KIT mutations. Most of these mutations affect the KIT juxtamembrane domain, but other KIT domains are mutated at a lower frequency. In this study, frequency of GCC TAT insertion mutation (1530ins6) in KIT exon 9 (extracellular domain) and its possible clinicopathologic significance was investigated. Screening of 520 GISTs identified 26 cases with 1530ins6 KIT mutation and confirmed the previously reported low frequency of this type of KIT mutation among GISTs of different locations. Of the 26 tumors with 1530ins6 KIT mutation studied, 21 originated from the small intestine, 1 from the colon, and 3 from the rectum. In 1 case, primary small intestinal versus colonic localization could not be clearly established because of intra-abdominal dissemination. No distinctive morphological features were identified for the cohort of tumors defined by 1530ins6 KIT mutations. Most of the tumors showed predominant spindle cell morphology, and a few cases had epithelioid or pleomorphic histological features. Following previously published criteria based on tumor size and mitotic rate, 22 of 26 (85%) tumors were classified as malignant or potentially malignant, and 4 (15%) were classified as probably benign. A malignant clinical course was documented in 18 of 19 tumors from the malignant category. The survival times of 11 patients who died of disseminated GISTs ranged from 1 month to 105 months (median survival time, 26 months). In contrast, 2 of 4 GISTs assigned as probably benign tumors with follow-up information had long disease-free survival. GISTs carrying 1530ins6 occur exclusively in the intestinal location, and a great majority of these tumors follow a malignant course.
Le séminome spermatocytaire est une tumeur rare, représentant moins de 1 % des cancers du testicule, survenant chez le sujet âgé. Nous rapportons 7 cas de cette entité. Les patients avaient un âge moyen de 66 ans. La tumeur se présentait comme une prolifération de cellules en nappes compactes, avec 3 types cellulaires, des cellules de petite taille, des cellules intermédiaires, des grandes cellules, et des figures de « spirèmes ». Il n’a été retrouvé ni contingent sarcomateux, ni séminome classique, ni d’autre contingent tumoral à cellules germinales. Dans les 7 cas, la tumeur restait intra-testiculaire. Dans le parenchyme péri tumoral, on ne notait pas de néoplasie intra-tubulaire à cellules germinales indéterminées. L’étude en immunohistochimie n’a retrouvé aucune expression des cellules tumorales avec tous les anticorps classiques testés (cytokératines, PLAP, marqueurs lymphoïdes) en dehors d’une positivité de tous les cas pour le c-kit (CD117) (100 %). Cette positivité membranaire était focale dans 4 cas, intense et diffuse dans les 3 autres. Le séminome spermatocytaire doit être reconnu, même devant une présentation inhabituelle, car son évolution est très favorable en l’absence d’un exceptionnel contingent sarcomateux, et ne nécessite qu’une simple orchidectomie. Une positivité avec le c-kit peut apporter une aide diagnostique.
The c-kit receptor tyrosine kinase (KIT) is activated upon ligand binding, thereby leading to a variety of signaling events that play a fundamental role in hematopoiesis. In addition to ligand-dependent activation, we have previously shown that KIT is constitutively activated in a ligand-independent manner by two point mutations, Val-559-->Gly (G559) mutation in the juxtamembrane domain and Asp-814-->Val (V814) mutation in the phosphotransferase domain. To investigate the biochemical consequence and biologic significance of these mutations, retroviral vectors encoding KITG559 or KITV814 were introduced into murine pro-B-type Ba/F3 cells and myeloid FDC-P1 cells, both of which require interleukin-3 (IL-3) for their growth and survival. In the cells, KITG559 or KITV814 were found to be constitutively phophorylated on tyrosine in the absence of stem cell factor (SCF) that is a ligand for KIT. Chemical cross-linking analysis showed that a substantial fraction of the phosphorylated KITG559 underwent dimerization even in the absence of SCF, whereas the phosphorylated KITV814 did not, suggesting the distinct mechanisms underlying constitutive activation of KIT by G559 and V814 mutations. Furthermore, the cells expressing either KITG559 or KITV814 were found to show a factor-independent growth, whereas the cells expressing wild-type KIT (KITWT) proliferated in response to SCF as well as IL-3. Moreover, subcutaneous injection of Ba/F3 cells expressing KITG559 or KITV814 into nude mice resulted in production of large tumors at all sites of the injection within 2 weeks, and all nude mice quickly succumbed to leukemia and died. These results suggest that, although the mechanisms underlying constitutive activation of KITG559 or KITV814 may be different, both of the activating mutations have a function to induce a factor-independent and tumorigenic phenotype. Also, the data of this study raise the possibility that the constitutively activating mutations of c-kit may play a causal role in development of hematologic malignancies.
The c-kit proto-oncogene encodes a receptor tyrosine kinase that is crucial to hematopoiesis, melanogenesis, and gametogeneis. Although the enzymatic activity of the c-kit product (KIT) is regulated by its ligand, both the Val559-->Gly (G559) mutation in the juxtamembrane domain and the Asp814-->Val (V814) mutation in the phosphotransferase domain lead to constitutive activation of KIT. By retroviral infection of hematopoietic progenitor cells with KIT(G559) or KIT(V814), KIT(G559) induced development of granulocyte/macrophage and mast-cell colonies in vitro without the addition of exogenous growth factors. KIT(V814) induced factor-independent growth of various types of hematopoietic progenitor cells, resulting in the development of mixed erythroid/myeloid colonies in addition to granulocyte/macrophage and mast-cell colonies. Furthermore, transplantation of KIT(G559) and KIT(V814)-infected bone marrow cells led to development of acute leukemia in one of 10 and six of 10 transplanted mice, respectively. No mice developed hematologic malignancies after transplantation of wild-type KIT-infected cells. Furthermore, transgenic mice expressing KIT(V814) developed acute leukemia or malignant lymphoma. These results demonstrate a direct role of the mutant KITs, particularly KIT(V814), in tumorigenesis of hematopoietic cells and suggest that similar mutations may contribute to the development of human hematologic malignancies.
Stem cell factor (SCF), also known as mast cell growth factor, kit ligand, and steel factor, is the ligand for the tyrosine kinase receptor (SCFR) that is encoded by the c-kit proto-oncogene. We analyzed the effects of recombinant human SCF (r-hSCF, 5-50 micrograms/kg/day, injected subcutaneously) on mast cells and melanocytes in a phase I study of 10 patients with advanced breast carcinoma. A wheal and flare reaction developed at each r-hSCF injection site; by electron microscopy, most dermal mast cells at these sites exhibited extensive, anaphylactic-type degranulation. A 14-d course of r-hSCF significantly increased dermal mast cell density at sites distant to those injected with the cytokine and also increased both urinary levels of the major histamine metabolite, methyl-histamine, and serum levels of mast cell alpha-tryptase. Five subjects developed areas of persistent hyperpigmentation at r-hSCF injection sites; by light microscopy, these sites exhibited markedly increased epidermal melanization and increased numbers of melanocytes. The demonstration that r-hSCF can promote both the hyperplasia and the functional activation of human mast cells and melanocytes in vivo has implications for our understanding of the role of endogenous SCF in health and disease. These findings also indicate that the interaction between SCF and its receptor represents a potential therapeutic target for regulating the numbers and functional activity of both mast cells and cutaneous melanocytes.
Both stem cells and mast cells express c-kit and proliferate after exposure to c-kit ligand. Mutations in c-kit may enhance or interfere with the ability of c-kit receptor to initiate the intracellular pathways resulting in cell proliferation. These observations suggested to us that mastocytosis might in some patients result from mutations in c-kit. cDNA synthesized from peripheral blood mononuclear cells of patients with indolent mastocytosis, mastocytosis with an associated hematologic disorder, aggressive mastocytosis, solitary mastocytoma, and chronic myelomonocytic leukemia unassociated with mastocytosis was thus screened for a mutation of c-kit. This analysis revealed that four of four mastocytosis patients with an associated hematologic disorder with predominantly myelodysplastic features had an A-->T substitution at nt 2468 of c-kit mRNA that causes an Asp-816-->Val substitution. One of one patient examined who had mastocytosis with an associated hematologic disorder had the corresponding mutation in genomic DNA. Identical or similar amino acid substitutions in mast cell lines result in ligand-independent autophosphorylation of the c-kit receptor. This mutation was not identified in the patients within the other disease categories or in 67 of 67 controls. The identification of the point mutation Asp816Val in c-kit in patients with mastocytosis with an associated hematologic disorder provides insight not only into the pathogenesis of this form of mastocytosis but also into how hematopoiesis may become dysregulated and may serve to provide a means of confirming the diagnosis, assessing prognosis, and developing intervention strategies.
The c-kit proto-oncogene encodes a receptor tyrosine kinase that is known to play a crucial role in mast cell growth and differentiation. In a human mast cell leukemia cell line (HMC-1), KitR was found to be constitutively phosphorylated on tyrosine, activated and associated with phosphatidylinositol 3-kinase (P13K) in the absence of autocrine production of SCF. Sequencing of c-kit cDNA revealed that c-kit genes of HMC-1 cells were composed of a normal, wild-type allele and a mutant allele with two point mutations in codon 560 and codon 816, resulting in intracellular amino acid substitutions of Gly-560 for Val and Val-816 for Asp, respectively. Murine c-kit mutants encoding Gly-559 and/or Val-814, corresponding to human Gly-560 and/or Val-816, were constructed by site-directed mutagenesis and expressed in cells of a human embryonic kidney cell line (293T). In the transfected cells, KitR (Gly-559 + Val-814) and KitR (Val-814) were strikingly phosphorylated on tyrosine and activated in the absence of SCF, whereas tyrosine phosphorylation and activation of KitR (Gly-559) or wild-type KitR was modest or little, respectively. These results suggest that constitutive activation of KitR in HMC-1 results from the activating mutations of c-kit gene, and raise the possibility that the activating mutations, particularly at codon 814 of murine c-kit or at codon 816 of human c-kit, may participate in oncogenesis of mast cells.
Mast cells may be cultured from human peripheral blood in the presence of recombinant human stem cell factor (rhSCF). The characteristics of the cells in peripheral blood that give rise to mast cells are unknown. Because mast cell precursors in human marrow are CD34+, human peripheral blood mononuclear cells from patients with mastocytosis and normal controls were sorted on the basis of CD34 expression and the positive and negative cell populations were cultured in rhSCF, recombinant human interleukin-3 (rhIL-3), or both for 6 weeks. Cell cultures were examined every 2 weeks for total and mast cell number and cell differential using Wright Giemsa and acid toluidine blue stains and antibodies to mast cell tryptase and chymase, cell-associated histamine, and expression of CD34, c-kit, Fc epsilon RI, and Fc gamma RII using flow cytometric analysis. The ultrastructural anatomy of mast cells was examined by electron microscopy. Peripheral blood CD34+ cells cultured in rhSCF with or without rhIL-3 gave rise to cell cultures consisting of greater than 80% mast cells by 6 weeks. CD34+ cells cultured in rhIL-3 alone did not give rise to mast cells, whereas rhIL-3 plus rhSCF increased the final mast cell number eightfold when compared with cells cultured in rhSCF alone. Mast cells increased concomitantly with a decrease in large undifferentiated mononuclear cells. CD34- cells did not give rise to mast cells. Histamine content per cell at 6 weeks was approximately 5 pg. Electron microscopy of 4-week cultures showed immature mast cells containing predominantly tryptase-positive granules that were either homogeneous or contained lattice structures, partial scroll patterns, or central dense cores and mixtures of vesicles, fine granular material, and particles. The CD34+ population at day 0 expressed Kit (65%) and Fc gamma RII (95%), but not Fc epsilon RI, by fluorescence-activated cell sorter analysis. At 6 weeks, CD34+-derived mast cells exhibited Fc epsilon RI in addition to Kit and Fc gamma RII, and were negative for CD34 antigen. Patients with mastocytosis showed a higher number of mast cells per CD34+ cell cultured compared with normal controls. Thus, the mast cell precursor in human peripheral blood is CD34+/Fc epsilon RI- and gives rise to mast cells in the presence of rhSCF with or without rhIL-3, and the number of mast cells arising per CD34+ cell in culture is greater when the CD34+ cells are obtained from patients with mastocytosis compared with normal subjects.
Despite extensive research on the molecular mechanisms of signal transduction by growth factors and their oncogenic receptor tyrosine kinases, the physiological relevance of these pathways, especially in mammals, remains largely unknown. A unique exception is the Steel factor (SLF) and its c-kit-encoded receptor, because many natural germ line mutations of both the ligand and the receptor exist in mice. The protooncogene c-kit encodes a cell surface receptor that belongs to the immunoglobulin gene family and carries an intrinsic tyrosine kinase activity in its cytoplasmic portion. The precursor of the Kit ligand, SLF, is also a transmembrane protein that exists as a soluble factor as well as a cell surface protein. The interaction of Kit with SLF leads to receptor dimerization, kinase activation, and tyrosine phosphorylation of cytoplasmic proteins that contain Src homology 2 motifs. Various mutations in Kit and SLF result in a defective signaling pathway and underly the complex phenotypes of W and Sl mice, respectively. The early development of at least four cell lineages is affected. These are erythrocytes, melanocytes, germ cells, and mast cells. Correlation between the behavior of these lineages and specific mutations uncovered interesting physiological aspects of the mechanism of signal transduction by a polypeptide growth factor. These include the different degrees of severity of affected lineages, indications for distinct functions during early embryonic development and at late phases, the significance of synergy between a growth factor and lymphokines, the interaction between mutant and wild-type proteins in heterozygous animals, and the possibility that a surface-anchored ligand may act differently than a soluble factor. Predictably, the lessons learned with Kit and Sl mice will be widely relevant to other pairs of ligands and receptors that control the function of different cell lineages and physiological processes.
More than 127 loci are actually known to affect pigmentation in mouse when they are mutated. From embryogenesis to transfer of melanin to the keratinocytes or melanocytes survival, any defect is able to alter the pigmentation process. Many gene mutations are now described, but the function of their product protein and their implication in melanogenesis are only partially understood. Each genetic pigmentation disorder brings new clues in the understanding of the pigmentation process. According to the main genodermatoses known to induce hypo- or hyperpigmentation, we emphasize in this review the last advances in the understanding of the physiopathology of these diseases and try to connect, when possible, the mutation to the clinical phenotype.
The lesions of cutaneous mastocytosis are characterized by dermal infiltrates of mast cells and may appear hyperpigmented because of the presence of increased levels of epidermal melanin. Mast-cell growth factor, the ligand for the product of the c-kit proto-oncogene, stimulates the proliferation of mast cells and increases the production of melanin by melanocytes. We therefore looked for the expression of the mast-cell growth factor gene in the skin of patients with cutaneous mastocytosis using immunohistochemical techniques and the polymerase chain reaction.
In the skin of normal subjects and those with unrelated diseases, immunoreactive mast-cell growth factor was associated with keratinocytes and scattered dermal cells, a pattern consistent with cell-bound mast-cell growth factor. In skin samples containing lesions and in clinically normal skin from patients with mastocytosis, however, mast-cell growth factor was also found free in the dermis and in the extracellular spaces between keratinocytes, suggesting the presence of a soluble form of this protein. Messenger RNA (mRNA) that can encode soluble mast-cell growth factor was present in the skin of patients as well as in that of normal control subjects. No sequence abnormalities were detected in mRNA for mast-cell growth factor from one patient.
The altered distribution of mast-cell growth factor in the skin of patients with cutaneous mastocytosis is consistent with abnormal production of the soluble form of this factor. This abnormality is probably due to increased proteolytic processing, since it was not explained by differences in the splicing or sequence of mast-cell growth factor mRNA in the patients. Soluble mast-cell growth factor may cause the characteristic accumulation of mast cells and the hyperpigmentation of skin found in cutaneous mastocytosis. These findings suggest that some forms of mastocytosis represent reactive hyperplasia rather than mast-cell neoplasia.
Mastocytosis is characterized by accumulations of mast cells in various organs (1). Most cases are indolent and confined to the skin, where discrete mast cell infiltrates are associated increased epidermal melanin, a clinical picture known as urticaria pigmentosa (UP). Other forms of mastocytosis combine UP with aggressive involvement of other organs or with haemotologic abnormalities (1-4). It is not known whether all forms of mastocytosis are true neoplasms or whether some might represent reactive hyperplasias (5-7). The c-KIT proto-oncogene encodes a type III receptor tyrosine kinase (KIT) that is critical to the development and survival of mast cells and melanocytes (8-11). The ligand for KIT (KL) can stimulate mast cell development, proliferation, and mediator release (9,12-17), as well as melanocyte proliferation and pigment production (18-20). To determine the role of c-KIT in the pathogenesis of mastocytosis, we examined tissue and cells isolated from a patient with UP and aggressive systemic mastocytosis with massive splenic involvement. We found a mutation that results in constitutive activation and expression of c-KIT in mast cells of both skin and spleen. This is the first in situ demonstration of an activation c-KIT mutation in neoplastic cells. It also demonstrates the clonal and neoplastic nature of this form of mastocytes.
Systemic mast cell disease (SMCD) is a disorder characterized by a mast cell proliferation in various tissues. Mast cells express the c-kit proto-oncogene. A few cases of c-kit mutations have been described in SMCD. We report an aggressive SMCD in a patient who presented with a bone marrow infiltration by abnormal mast cells. Molecular studies of mast cell DNA and RNA revealed a new c-kit heterozygous mutation (Asp820Gly). This mutation leads to a drastic amino-acid change and is located close to the highly oncogenic Asp816Val. These findings suggest that the Asp820Gly has a potential role in c-kit activation.