Pathogenesis Of Gastrointestinal Stromal Tumors Research Articles

Metastasectomy for gastrointestinal stromal tumors

Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the intestinal tract. Improvements in understanding the molecular pathogenesis of GIST have resulted in novel treatment strategies combining surgery with tyrosine kinase inhibitors (TKIs). Metastasectomy in carefully selected patients who have stable or responsive disease on imatinib should be considered in the multidisciplinary setting. We review existing data on surgical cytoreduction in metastatic GIST while on targeted therapy and compare outcomes with either treatment alone.

Surgical treatment of GIST – An institutional experience of a high-volume center

BackgroundDiscovery of the molecular pathogenesis of Gastrointestinal stromal tumors led to the development of targeted therapies, revolutionizing their treatment. However, surgery is still the mainstay of GIST therapy and the only chance for cure. AimHere we present a single institutional consecutive case series of 159 GIST-patients. Methods and patientsA total of 159 GIST-patients who underwent resection between 1994 and 2011 were reviewed for clinicopathohistological data, informations on surgical and medical therapy and further follow-up, outcome and survival data. ResultsLaparoscopic (25.2%) and open (71.1%) GIST surgery achieved complete resection rates of 97.5% and 85.2%, whereas 44.4% of incomplete and 6.6% of complete resected patients died from GIST. Compared to open surgery laparoscopy significantly reduced duration of operation (183.4 vs. 130.6 min), length of hospitalization (16.1 vs. 8.3 d) and morbidity (23% vs. 7.5%). Mean survival time was 3.7 ± 2.7 years (R0: 5.1 a and R1: 2.6 a) and the mean overall survival was 4.5 ± 3.8 years. ConclusionComplete surgical resection is the primary goal and laparoscopy can be performed safely in a subset of GIST-patients with potential perioperative advantages. Although not proven by the present study the authors assume that multimodal GIST-treatment, as performed in reference-centers, is required for advanced or high risk disease. Our data suggest the potential for minimally invasive GIST resection to achieving comparable oncological outcomes as after open surgery while providing low morbidity rates.

Surgeon's role for gastric gastrointestinal stromal tumor in imatinib era

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor arising in the stomach, which is characterized by the protein-tyrosine kinase KIT (CD117) expression. Historically, surgical resection has been the mainstay of the curative treatment for localized primary tumors. However, more than an half of the patients with GISTs subsequently develop recurrence or metastasis. The discovery of the molecular pathogenesis of GIST led to the remarkable development of the molecular-targeted therapy with imatinib mesylate, a specific tyrosine kinase inhibitor, and the clinical management of GISTs has rapidly evolved during the last decade. As imatinib has demonstrated significant response in most metastatic GIST, it became the standard first line treatment in patients with metastatic or unresectable GISTs. Nonetheless, treating GIST with a single agent alone is proven to have many limitations because of development of imatinib resistance. Surgical resection still remains the only chance for a cure in GIST treatment. A key strategy for prolonging the survival of patients with GIST is to improve the outcome of surgery. Imatinib use in the GIST management may contribute to surgeons’ success in attaining this objective. It is clear that GIST is a complex disease, and a multidisciplinary approach with effective integration of surgery and targeted therapy is crucial to offer a better prognosis to the patients.

Post-Transcriptional Dysregulation by miRNAs Is Implicated in the Pathogenesis of Gastrointestinal Stromal Tumor [GIST

In contrast to adult mutant gastrointestinal stromal tumors [GISTs], pediatric/wild-type GISTs remain poorly understood overall, given their lack of oncogenic activating tyrosine kinase mutations. These GISTs, with a predilection for gastric origin in female patients, show limited response to therapy with tyrosine kinase inhibitors and generally pursue a more indolent course, but still may prove fatal. Defective cellular respiration appears to underpin tumor development in these wild-type cases, which as a group lack expression of succinate dehydrogenase [SDH] B, a surrogate marker for respiratory chain metabolism. Yet, only a small subset of the wild-type tumors show mutations in the genes coding for the SDH subunits [SDHx]. To explore additional pathogenetic mechanisms in these wild-type GISTs, we elected to investigate post-transcriptional regulation of these tumors by conducting microRNA (miRNA) profiling of a mixed cohort of 73 cases including 18 gastric pediatric wild-type, 25 (20 gastric, 4 small bowel and 1 retroperitoneal) adult wild-type GISTs and 30 gastric adult mutant GISTs. By this approach we have identified distinct signatures for GIST subtypes which correlate tightly with clinico-pathological parameters. A cluster of miRNAs on 14q32 show strikingly different expression patterns amongst GISTs, a finding which appears to be explained at least in part by differential allelic methylation of this imprinted region. Small bowel and retroperitoneal wild-type GISTs segregate with adult mutant GISTs and express SDHB, while adult wild-type gastric GISTs are dispersed amongst adult mutant and pediatric wild-type cases, clustering in this situation on the basis of SDHB expression. Interestingly, global methylation analysis has recently similarly demonstrated that these wild-type, SDHB-immunonegative tumors show a distinct pattern compared with KIT and PDGFRA mutant tumors, which as a rule do express SDHB. All cases with Carney triad within our cohort cluster together tightly.

Clinical significance of Insulin-Growth Factor 1 and Insulin-Growth Factor 1 Receptor expression in Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal tract and are mostly driven by KIT and PDGFRA-activation mutations. However, other signaling pathways are involved in pathogenesis and proliferation of GISTs. This study investigates the prognostic significance of insulin-like growth factor 1 (IGF1) and IGF1 receptor (IGF1R) and the role of succinate dehydrogenase subunit B (SDHB) in GISTs. Immunohistochemistry (IHC) for IGF1, IGF1R and SDHB was performed in total of 165 GISTs. The overexpression of IGF1 was evident in tumors with high mitotic count, large tumor size and was correlated with high risk of malignant behavior. IGF1R overexpression was correlated with IGF overexpression, high mitotic count and high risk of malignant behavior. Loss of expression for SDHB was found in only 2 gastric GISTs. The overexpression of IGF1 and IGF1R can be useful marker to predict relapse and aggressive behavior in GISTs and has prognostic implications.

Altered angiogenesis gene expression in gastrointestinal stromal tumors: potential use in diagnosis, outcome prediction, and treatment

Gastrointestinal stromal tumors (GISTs) occur in diverse locations of the gastrointestinal system. We studied the pathogenesis of GIST by measurement of microvascular density (MVD) and expression of nine signal transduction molecules that have known roles in diverse types of cancers (PI3K, Akt, pTEN, uPA, MMP2, MMP9, HIF1, NOS2, and VEGF) in the tumorous tissues and adjacent normal tissues of 124 GIST patients. We also compared the MVD (a measure of angiogenesis) in tumorous and adjacent normal tissues. Our results indicated significant differences in the expression of the assayed mRNAs and proteins in GIST cells and in adjacent normal cells. In addition, tumorous tissues had significantly higher MVD than adjacent normal tissues. These nine genes have potential for use for diagnosis, outcome prediction, and as new targeted treatments for GISTs.

Gastrointestinal Stromal Tumors: Clinicopathology and Advances in Molecular Pathogenesis

Gastrointestinal stromal tumors (GISTs) are common mesenchymal neoplasms in the gastrointestinal (GI) tract that need to be differentiated from other GI mesenchymal tumors. They often present with heterogeneous features based on the anatomic locations, histomorphology and gene mutation status, which may lead to diagnostic and treatment challenges. Over the past decade, numerous studies revealed that KIT and PDGFRα tyrosine kinase pathways play key roles in the molecular pathogenesis of GISTs. Subsequently, specific biomarkers, such as CD117 and DOG1, have been developed and greatly improved the diagnostic accuracy. Moreover, advances in understanding the molecular nature of GISTs also provide valuable therapeutic targets. Two tyrosine kinase inhibitors, Imatinib and Sunitinib, have currently been approved for treating patients with advanced and metastatic GISTs. [N A J Med Sci. 2012;5(2):94-102.]

Gastrointestinal Stromal Tumor: Advances in Diagnosis and Management

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract and should be differentiated from other mesenchymal tumors. They harbor specific activating mutations in the KIT or platelet-derived growth factor receptor α ( PDGFRA ) receptor tyrosine kinases, which makes them responsive to pharmacologic inhibitors, such as imatinib mesylate and sunitinib malate. To provide a comprehensive review of the pathogenesis of GIST and the underlying principles of targeted therapy, to review the salient histologic and immunohistochemical features that facilitate the distinction of GIST from other mesenchymal neoplasms of the gastrointestinal tract, and to present the prognostic parameters for risk stratification that guide clinical management. Review of the English literature through PubMed as well as personal experience. Photographs were taken from cases encountered at the Cleveland Clinic. The discovery of the KIT -GIST connection has not only improved the diagnostic accuracy of GISTs but also provided us with a better understanding of the histogenesis and molecular pathogenesis of these neoplasms.

Gastrointestinal Stromal Tumors: Disease and Treatment Update

Gastrointestinal Stromal Tumors: Disease and Treatment Update

Differential Properties of Current Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors

During the past decade, tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of gastrointestinal stromal tumors (GIST), providing new treatment options with unprecedented clinical benefit. Recognition of the key role played by the receptor tyrosine kinases KIT and platelet-derived growth factor receptor alpha (PDGFRα) in the pathogenesis of GIST led to the development of imatinib, the first TKI for this indication and the current first-line standard of care for unresectable or metastatic GIST. However, the clinical efficacy of imatinib is limited by two concerns: the rare patient-specific intolerance to the drug, and the fact that the majority of patients will eventually develop treatment-refractory disease that is resistant to this selective TKI. Although sunitinib has been approved worldwide as second-line therapy for GIST following failure of imatinib, the benefits of sunitinib in treating GIST following imatinib failure are most often more limited than first-line therapy, with emergence of treatment-resistant disease in less than 1 year. Other TKIs studied in clinical trials for GIST include a wide range of different agents, such as sorafenib, dasatinib, pazopanib, regorafenib, masitinib, and nilotinib. Each agent differs in its selectivity for individual tyrosine kinases, conferring each with distinct properties that determine clinical safety and efficacy. No agent has yet reached regulatory approval for management of GIST following the failure of both imatinib and sunitinib. This review highlights relevant differences and similarities in the structures and functions, including kinase selectivity and mechanisms of binding, of the currently approved TKIs and certain others in development for the treatment of advanced GIST. In addition, the ability of some TKIs to inhibit alternative targets with potency similar to or greater than their intended primary target (pleiotropic effects) is also discussed.

New molecular targets beyond KIT and PDGFRA in gastrointestinal stromal tumors: present and future

Introduction: The biological complexity of gastrointestinal stromal tumors (GISTs) and the concomitant increase in patients' life expectancy have enhanced the need for new therapeutic options to overcome the development of primary and secondary resistance to tyrosine kinase inhibitors. Aided by more sophisticated molecular biology techniques, researchers have recently sought to identify new therapeutic targets with a defined role in GISTs pathogenesis and a potential application in clinical practice.Areas covered: The first aim of this review is to describe new targets and drugs in GISTs, alone or in combination, both in pre-clinical and clinical settings. The second aim is to discuss the criticism in this field, the role of molecular biology, and future perspectives in light of the recent development of more sophisticated whole-genomic technologies.Expert opinion: Several targets involved in GIST pathogenesis have been identified and novel biological drugs have recently been developed, offering new treatment options in the scenario of GIST therapy. However, the identification of new therapeutic targets represents a long process and requires a global overview of the problem and a multi-step approach to convert an initial intuition or casual finding into a systematic analytical process.

Targeted therapy in GIST: in silico modeling for prediction of resistance

Elucidation of the genetic processes leading to neoplastic transformation has identified cancer-promoting molecular alterations that can be selectively targeted by rationally designed therapeutic agents. Protein kinases are druggable targets and have been studied intensively. New methodologies--including crystallography and three-dimensional modeling--have allowed the rational design of potent and selective kinase inhibitors that have already reached the clinical stage. However, despite the clinical success of kinase-targeted therapies, most patients that respond eventually relapse as a result of acquired resistance. Darwinian-type selection of secondary mutations seems to have a major role in this resistance. The emergence and/or expansion of tumor clones containing new mutations in the target kinase and that are drug-insensitive have been observed after chronic treatment. The resistance mechanisms to tyrosine kinase inhibitors, in particular secondary resistant mutations as a consequence of treatment, will be discussed in detail. In particular, this Review will focus on KIT and PDGFRA mutations, which are involved in the pathogenesis of gastrointestinal stromal tumors. Harnessing the selection of mutated variants developed to overcome these resistance mechanisms is an ongoing goal of current research and new strategies to overcome drug resistance is being envisaged.

Succinate Dehydrogenase Subunit B (SDHB) Is Expressed in Neurofibromatosis 1-Associated Gastrointestinal Stromal Tumors (Gists): Implications for the SDHB Expression Based Classification of Gists

Gastrointestinal Stromal Tumor (GIST) is the most common mesenchymal tumor of the digestive tract. GISTs develop with relatively high incidence in patients with Neurofibromatosis-1 syndrome (NF1). Mutational activation of KIT or PDGFRA is believed to be a driving force in the pathogenesis of familial and sporadic GISTs. Unlike those tumors, NF1-associated GISTs do not have KIT or PGDFRA mutations. Similarly, no mutational activation of KIT or PDGFRA has been identified in pediatric GISTs and in GISTs associated with Carney Triad and Carney-Stratakis Syndrome. KIT and PDGFRA-wild type tumors are expected to have lesser response to imatinib treatment. Recently, Carney Triad and Carney-Stratakis Syndrome -associated GISTs and pediatric GISTs have been shown to have a loss of expression of succinate dehydrogenase subunit B (SDHB), a Krebs cycle/electron transport chain interface protein. It was proposed that GISTs can be divided into SDHB- positive (type 1), and SDHB-negative (type 2) tumors because of similarities in clinical features and response to imatinib treatment. In this study, SDHB expression was examined immunohistochemically in 22 well-characterized NF1-associated GISTs. All analyzed tumors expressed SDHB. Based on SDHB-expression status, NF1-associated GISTs belong to type 1 category; however, similarly to SDHB type 2 tumors, they do not respond well to imatinib treatment. Therefore, a simple categorization of GISTs into SDHB-positive and-negative seems to be incomplete. A classification based on both SDHB expression status and KIT and PDGFRA mutation status characterize GISTs more accurately and allow subdivision of SDHB-positive tumors into different clinico-genetic categories.

A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number

In addition to KIT and PDGFRA mutations, sequential accumulation of other genetic events is involved in the development and progression of gastrointestinal stromal tumors (GISTs). Until recently, the significance of these other alterations has not been thoroughly investigated. We report the first study that integrates gene expression profiling and high-resolution genomic copy number analyses in GIST. Fresh tissue specimens from 25 patients with GIST were collected, and gene expression profiling and high-resolution genomic copy number analyses were performed, using Affymetrix U133Plus and SNP array 6.0. We found that all 21 mutant GIST patients showed both macroscopic cytogenetic alterations and cryptic microdeletions or amplifications, whereas 75% (three of four) of wild-type patients with GIST did not show genomic imbalances. The most frequently observed chromosomal alterations in patients with mutant GIST included 14q complete or partial deletion (17 of 25), 1p deletion (14 of 25) and 22q deletion (10 of 25). Genetic targets of the chromosomal aberrations were selected by integrated analysis of copy number and gene expression data. We detected the involvement of known oncogenes and tumor suppressors including KRAS in chr 12p amplification and KIF1B, PPM1A, NF2 in chr 1p, 14q and 22p deletions, respectively. The genomic segment most frequently altered in mutated samples was the 14q23.1 region, which contains potentially novel tumor suppressors, including DAAM1, RTN1 and DACT1. siRNA-mediated RTN1 downregulation showed evidence for the potential role in GIST pathogenesis. The combination of gene expression profiling and high-resolution genomic copy number analysis offers a detailed molecular portrait of GISTs, providing an essential comprehensive knowledge necessary to guide the discovery of novel target genes involved in tumor development and progression.

Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors

BackgroundActivating mutations in Kit receptor tyrosine kinase or the related platelet-derived growth factor receptor (PDGFR) play an important role in the pathogenesis of gastrointestinal stromal tumors (GIST).MethodsThis study investigated the activity of motesanib, an inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3; PDGFR; and Kit, against primary activating Kit mutants and mutants associated with secondary resistance to imatinib. Single- and double-mutant isoforms of Kit were evaluated for their sensitivity to motesanib or imatinib in autophosphorylation assays and in Ba/F3 cell proliferation assays.ResultsMotesanib inhibited Kit autophosphorylation in CHO cell lines expressing primary activating mutations in exon 9 (AYins503-504, IC50 = 18 nM) and exon 11 (V560 D, IC50 = 5 nM; Δ552-559, IC50 = 1 nM). Motesanib also demonstrated activity against kinase domain mutations conferring imatinib resistance (V560D/V654A, IC50 = 77 nM; V560D/T670I, IC50 = 277 nM; Y823 D, IC50 = 64 nM) but failed to inhibit the imatinib-resistant D816V mutant (IC50 > 3000 nM). Motesanib suppressed the proliferation of Ba/F3 cells expressing Kit mutants with IC50 values in good agreement with those observed in the autophosphorylation assays.ConclusionsIn conclusion, our data suggest that motesanib possesses inhibitory activity against primary Kit mutations and some imatinib-resistant secondary mutations.

Essential Requirement for PP2A Inhibition by the Oncogenic Receptor c-KIT Suggests PP2A Reactivation as a Strategy to Treat c-KIT+ Cancers

Oncogenic mutations of the receptor tyrosine kinase c-KIT play an important role in the pathogenesis of gastrointestinal stromal tumors, systemic mastocytosis, and some acute myeloid leukemias (AML). Although juxtamembrane mutations commonly detected in gastrointestinal stromal tumor are sensitive to tyrosine kinase inhibitors, the kinase domain mutations frequently encountered in systemic mastocytosis and AML confer resistance and are largely unresponsive to targeted inhibition by the existing agent imatinib. In this study, we show that myeloid cells expressing activated c-KIT mutants that are imatinib sensitive (V560G) or imatinib resistant (D816V) can inhibit the tumor suppressor activity of protein phosphatase 2A (PP2A). This effect was associated with the reduced expression of PP2A structural (A) and regulatory subunits (B55alpha, B56alpha, B56gamma, and B56delta). Overexpression of PP2A-Aalpha in D816V c-KIT cells induced apoptosis and inhibited proliferation. In addition, pharmacologic activation of PP2A by FTY720 reduced proliferation, inhibited clonogenic potential, and induced apoptosis of mutant c-KIT(+) cells, while having no effect on wild-type c-KIT cells or empty vector controls. FTY720 treatment caused the dephosphorylation of the D816V c-KIT receptor and its downstream signaling targets pAkt, pSTAT5, and pERK1/2. Additionally, in vivo administration of FTY720 delayed the growth of V560G and D816V c-KIT tumors, inhibited splenic and bone marrow infiltration, and prolonged survival. Our findings show that PP2A inhibition is essential for c-KIT-mediated tumorigenesis, and that reactivating PP2A may offer an attractive strategy to treat drug-resistant c-KIT(+) cancers.

Gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) have emerged from being poorly defined, treatment-resistant tumors to a well-recognized, well-understood, and treatable tumor entity within only one decade. The understanding of GIST biology has made this tumor a paradigm for molecularly targeted therapy in solid tumors and provides informative insights into the advantages and limitations of so-called targeted therapeutics. Approximately 85% of GISTs harbor activating mutations in KIT or the homologous receptor tyrosine kinase PDGFRA gene. These mutations are an early event in GIST development and the oncoproteins serve as a target for the small molecule tyrosine kinase inhibitors imatinib and sunitinib. The existing and emerging treatment options demand exact morphologic classification and risk assessment. Although, KIT (CD117) immunohistochemistry is a reliable diagnostic tool in the diagnosis of GIST, KIT-negative GISTs, GISTs showing unusual morphology as well as GISTs which progress during or after treatment with imatinib/sunitinib can be a challenge for pathologists and clinicians. This review focuses on GIST pathogenesis, morphologic evaluation, promising new immunohistochemical markers, risk assessment, the role of molecular analysis, and the increasing problem of secondary imatinib resistance and its mechanisms.

Molecular basis and management of gastrointestinal stromal tumors

Molecularly targeted agents have dramatically impacted the management of several cancers. Targeting KIT has led to a new treatment paradigm in gastrointestinal stromal tumors (GISTs). KIT is a cell surface receptor with tyrosine kinases that, upon binding of its ligand, stem cell factor, activates various signaling pathways. Imatinib and sunitinib, both tyrosine kinase inhibitors directed to KIT, were approved for first- and second-line treatment of metastatic and unresectable GISTs. In this article, we will review the molecular pathogenesis of GISTs followed by a discussion of imatinib and sunitinib's role in the treatment of GISTs. Finally, we will introduce novel therapeutic options for imatinib- and sunitinib-resistant GISTs.

124 Gastro-intestinal stromal tumors (GIST): the model for solid tumors treated with tyrosine kinase inhibitors

Recent studies have done much to reveal the biological and genetic underpinnings of gastrointestinal stromal tumors (GISTs). Constitutive activation of the KIT receptor tyrosine kinase is a central pathogenetic event in most GISTs and generally results from oncogenic point mutations which can involve either extracellular or cytoplasmic domains of the receptor. Oncogenic mutations enable the KIT receptor to phosphorylate various substrate proteins, leading to activation of signal transduction cascades which regulate cell proliferation, apoptosis, chemotaxis, and adhesion. KIT mutations can be broadly assigned to 2 groups, those that involve the “regulatory” regions responsible for modulating KIT enzymatic activity and those that involve the enzymatic region itself. In vitro studies suggest that GISTs with regulatory-region KIT mutations are more likely to respond to STI-571 than are GISTs with enzymatic-region mutations. A minority of GISTs lack demonstrable KIT mutations, but KIT is nonetheless strongly activated. Such GISTs might contain KIT mutations which are not readily detected by conventional screening methods, or alternately, KIT might be activated by nonmutational mechanisms. Most GISTs have noncomplex cytogenetic profiles, often featuring deletions of chromosomes 14 and 22. Additional chromosomal aberrations are acquired as the GISTs progress to higher histologic grade. These cytogenetic aberrations are undoubtedly important in GIST pathogenesis, but currently they do not play a key role as diagnostic adjuncts. HUM PATHOL 33:484-495. Copyright 2002, Elsevier Science (USA). All rights reserved.

High density DNA array analysis reveals distinct genomic profiles in a subset of gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) generally harbor activating mutations in KIT or platelet-derived growth facter receptor (PDGFRA). Mutations in these receptor tyrosine kinases lead to dysregulation of downstream signaling pathways that contribute to GIST pathogenesis. GISTs with KIT or PDGFRA mutations also undergo secondary cytogenetic alterations that may indicate the involvement of additional genes important in tumor progression. Approximately 10-15% of adult and 85% of pediatric GISTs do not have mutations in KIT or in PDGFRA. Most mutant adult GISTs display large-scale genomic alterations, but little is known about the mutation-negative tumors. Using genome-wide DNA arrays, we investigated genomic imbalances in a set of 31 GISTs, including 10 KIT/PDGFRA mutation-negative tumors from nine adults and one pediatric case and 21 mutant tumors. Although all 21 mutant GISTs exhibited multiple copy number aberrations, notably losses, eight of the 10 KIT/PDGFRA mutation-negative GISTs exhibited few or no genomic alterations. One KIT/PDGFRA mutation-negative tumor exhibiting numerous genomic changes was found to harbor an alternate activating mutation, in the serine-threonine kinase BRAF. The only other mutation-negative GIST with significant chromosomal imbalances was a recurrent metastatic tumor found to harbor a homozygous deletion in chromosome arm 9p. Similar findings in several KIT-mutant GISTs identified a minimal overlapping region of deletion of approximately 0.28 Mbp in 9p21.3 that includes only the CDKN2A/2B genes, which encode inhibitors of cell-cycle kinases. These results suggest that GISTs without activating kinase mutations, whether pediatric or adult, generally exhibit a much lower level of cytogenetic progression than that observed in mutant GISTs.