Die diagnostische und prädiktive Bedeutung von Kit (CD117)

Abstract

KIT (CD117) is a 145-KD transmembrane glycoprotein that is the product of the kit-gene. As a member of the subclass III family of receptor tyrosine kinases, KIT is closely related to the receptors for platelet derived growth factor alpha and beta (PDGF-A and B), macrophage colony stimulating factor (M-CSF), and FLT3 ligand. The ligand for KIT, stem cell factor (SCF), also known as steel factor or mast cell growth factor promotes the dimerisation and autophosphorylation of KIT receptors. The phosphorylated tyrosine residues provide binding sites for signal molecules that contain SH2 domains. KIT mediated signal transduction is critical for the normal development and survival of haematopoietic progenitor cells, mast cells, interstitial cells of Cajal (intestinal pacemaker cells), melanocytes and germ cells. Upon differentiation, KIT expression is lost with the exception of mast cells, melanocytes and interstitial cells of Cajal. The detection of CD117 expression is of paramount diagnostic relevance in gastrointestinal stromal tumors (GIST). About 95% of all GISTs are immunohistochemically CD117 positive. The vast majority of all other sarcoma, carcinoma and also lymphoma are CD117 negative. Therefore, CD117 expression has a high sensitivity and specificity for the diagnosis of GIST. Moreover, activating mutations of KIT tyrosine kinase play a crucial pathogenetic role in GIST 80 to 85% of all GIST's contain activating mutations, primarily in Exon's 11 and 9 of the kit gene. Since the resulting mutant isoformes are sensitive to inhibition by imatinib (glivec), a specific tyrosine kinase inhibitor, the detection of a specific mutation has also a high predictive value. Besides GIST mastocytoses and seminomas are the neoplasias that most commonly express CD117. In contrast to GIST however, these two neoplasias contain mutations in different exons and are only partly imatinib sensitive. Moreover, CD117 expression is by no means entirely specific for these entities. It can also be detected in adenoid cystic carcinomas, thymic carcinomas and melanomas. Very rarely (< 5%) it can also be observed in other carcinomas and sarcomas. However, in the great majority of these cases with a CD117 protein expression there is no corresponding gene mutation of kit. Importantly, the lack of an activating mutation of KIT tyrosine kinase is good evidence that imatinib will not be effective. In other words, detection of sole CD117 protein expression is no solid basis for targeted therapy. The molecular pathological detection of CD117 expression in combination with the corresponding mutational status in patients with GIST (and other tumors) paradigmatically highlights the importance of modern molecular diagnostics in the era of targeted therapy.

CD117, Ki-67, and p53 predict survival in neuroendocrine carcinomas, but not within the subgroup of small cell lung carcinoma

“…CD117, the product of the c-kit gene, is a 145-kDa transmembrane glycoprotein belonging to the subclass III family of TKRs [1]. It is expressed in melanocytes, spermatogonia, breast epithelium, hematopoietic cells, interstitial cells of Cajal, and mast cells, where it is essential for maintaining normal hematopoiesis, gametogenesis, as well as growth and differentiation of other cells.…”

Platelet‐derived growth factor receptors and ligands are up‐regulated in paediatric fibromatoses

“…The fusion oncogene BCR–ABL in CML encodes the constitutively active BCR‐ABL tyrosine kinase, which leads to the substrate protein being activated by the phosphorylation of one of the tyrosine residues and subsequent activation of downstream effector molecules 33–35 . Inhibitors of kinase activity of ABL, c‐kit (CD117) and PDGFR such as imatinib, are thought to act by occupying the kinase ATP‐binding site, so that the kinase action is inhibited, preventing substrate phosphorylation, which prevents cell proliferation and tumorigenesis 21,23,31–33,36 . It has recently been reported that the PDGFR pathway is a major component in DFSP tumorigenesis 18,20 and imatinib has been shown to inhibit the growth of DFSP cells both in culture and in nude mice, with preliminary results from clinical trials appearing promising 37,38 .…”

“…[33][34][35] Inhibitors of kinase activity of ABL, c-kit (CD117) and PDGFR such as imatinib, are thought to act by occupying the kinase ATP-binding site, so that the kinase action is inhibited, preventing substrate phosphorylation, which prevents cell proliferation and tumorigenesis. 21,23,[31][32][33]36 It has recently been reported that the PDGFR pathway is a major component in DFSP tumorigenesis 18,20 and imatinib has been shown to inhibit the growth of DFSP cells both in culture and in nude mice, with preliminary results from clinical trials appearing promising. 37,38 Optimal treatment protocols…”

Gastrointestinal Stromal Tumors Short Review on KIT/PDGFRA Gene Mutations and Molecular Therapy

“…Recent studies have shown that the ligand for the c-kit receptor not only is stem-cell factor, but also steel factor. Mutations of KIT cause constitutive activation of the tyrosine kinase function of KIT [17]. Mutations can be subdivided into primary and secondary mutations.…”