T2 frequency, spectrum and in vitro sensitivity to imatinib. Clinically, all pdgframutated gists were located in the. Oncogenic mutations in kit or pdgfra have been identi. The postulated relationship between kitpdgfra mutations and their prognostic value in gastrointestinal stromal tumors gists has generated intense attention during the past decade, despite the fact that a great deal of studies have been conducted on this subject. Jan 31, 2003 most gastrointestinal stromal tumors gists have activating mutations in the kit receptor tyrosine kinase, and most patients with gists respond well to gleevec, which inhibits kit kinase activity.
These tumors arise from nerve cells in the wall of the gastrointestinal gi tract and can occur anywhere from the esophagus to. Gastrointestinal stromal tumors gists arup consult. Gists arise in the smooth muscle pacemaker interstitial cell of cajal, or similar cells. Pdf pdgfra mutations in gastrointestinal stromal tumors. The global gist network is a directory of resources available to people with gastrointestinal stromal tumors and their families. The latter mutations most often occur in gastric gists. Avapritinib for gastrointestinal stromal tumor with pdgfra. Purpose gastrointestinal stromal tumors gists commonly harbor oncogenic mutations of the kit tyrosine kinase, which is a target for the. There are approximately 5,000 new cases diagnosed each year and an evergrowing prevalence 1. The prognostic value of kit and pdgfra mutations in primary tumors is controversial. Sdha lossoffunction mutations in kit pdgfra wildtype.
Pdgfra gene mutations that lead to a constitutively active pdgfra protein are also associated with inflammatory fibroid polyps, which are small, noncancerous benign tumors that form in the gastrointestinal tract. Gastrointestinal stromal tumors gists are the most common mesenchymal tumor of the gastrointestinal tract, located mostly in the stomach 60% and small intestine 35%. These tumors arise from nerve cells in the wall of the gastrointestinal gi tract and can occur anywhere from the esophagus to the rectum. Bidirectional sequencing of exons 12 and 18 of the pdgfra plateletderived growth factor alpha gene. The tumors are thought to grow from specialized cells found in the gastrointestinal tract called interstitial cells of cajal iccs or precursors to these cells. Janewaya,1,2, su young kimb,1, maya lodishc, vania nosed, pierre rustine, jose gaalf, patricia l. The majority of gists show gainoffunction kit mutations.
Approximately 15% of gastrointestinal stromal tumors gist do not express kit mutations and of these about 5 to 7% harbor mutations in pdgfra. Carneystratakis syndrome, an inherited condition predisposing affected individuals to gastrointestinal stromal tumor gist and paraganglioma, is caused by germline mutations in succinate dehydrogenase sdh subunits b, c, or d, leading to dysfunction of complex ii of the electron transport chain. The number of new cases in the united states each year has been estimated at 5,0006,000. Gist may be noncancerous benign or cancerous malignant. Alk expressed in a gastrointestinal stromal tumor harboring. This is part one of a twopart series on kit and pdgfra kinase mutations in gist.
Mutation analysis of kit and pdgfra genes in gastrointestinal stromal tumors is gaining increasing importance for prognosis of gists and for prediction of treatment response. Gastrointestinal stromal tumors gists are the most common mesenchymal tumors in the gastrointestinal gi tract. Sep 21, 2016 purpose gastrointestinal stromal tumors gists commonly harbor oncogenic mutations of the kit tyrosine kinase, which is a target for the kinase inhibitor imatinib. Gastrointestinal stromal tumors gists for short are tumors that form in your gi tract. Gastrointestinal stromal tumors gists are the most common mesenchymal tumors of the intestinal track and are thought to originate from the interstitial cells of cajal iccs. Pdgfra exon 18 gastrointestinal stromal tumors gist. Exon 9 mutations 510% usually are 2codon 502503 duplications, and these occur predominantly in intestinal versus gastric gists. Gastrointestinal stromal tumors gists are the most common mesenchymal neoplasms of the gastrointestinal tract. Gastrointestinal stromal tumors gists with kit and pdgfra. Several groups have identified specific mutational subtypes in kit exon 11 associated with an increased risk of metastatic disease whereas gists with pdgfra mutations often behave less aggressive. Kit and pdgfra mutations in gastrointestinal stromal.
Abstract most gastrointestinal stromal tumors gists have activating mutations in the kit receptor tyrosine kinase, and most patients with gists respond well to gleevec, which inhibits kit kinase activity. Most gists are local when detected and are treated with surgery. Kit and pdgfra mutations in patients with gastrointestinal. To assess the diagnostic usefulness of denaturing highpressure liquid chromatography dhplc in this setting, we performed dhplc and dna sequencing to. Among gastric gists, tumors with deletions are more aggressive than those with point mutations. On january 9, 2020, avapritinib was approved for treatment of adults with unresectable or metastatic gastrointestinal stromal tumors gist harboring a plateletderived growth factor receptor alpha pdgfra exon 18 mutation, including d842v mutations. Gastrointestinal stromal tumors treatment adult pdq. Gleevec inhibits the constitutively activated form of the kit receptor tyrosine kinase, which is the critical transforming oncoprotein in more than 85% of gists. Gists are also seen in patients with somatic mutation in the kit gene. Prognostic relevance of kit and pdgfra mutations in. Symptoms depend on the location, size, and aggressiveness of the. Activating mutations in pdgfra are also involved in the development of 215% of the most common mesenchymal neoplasm of the gastrointestinal tract gi tract, viz. Tumors expressing kit or pdgfra oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression.
Sequence chromatograms of dna isolated from two patients with sporadic kitpdgfra wildtype gastrointestinal stromal tumors. Fda approves the first targeted therapy to treat a rare. This study is currently recruiting at multiple centers in the united states and europe. Most mutations are somatic in tumor tissue only, but patients with familial gist. Effect of kit and pdgfra mutations on survival in patients with. To provide a strong quantitative estimate of this postulated relationship, we carried out a metaanalysis which combined, compared. Purpose gastrointestinal stromal tumors gists commonly harbor oncogenic mutations of the kit tyrosine kinase, which is a target for the kinase inhibitor imatinib. Here, we aimed to assess whether kit and pdgfra mutations have survival impact in gastrointestinal stromal tumors gist. Prognostic value of kitpdgfra mutations in gastrointestinal.
Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking kit and pdgfra mutations katherine a. Pdgfra mutations usually occur in gastric gists, especially in the epithelioid variants. They are defined as tumors whose behavior is driven by mutations in the kit gene 85%, pdgfra gene 10%, or braf kinase rare. Gastrointestinal stromal tumors arog pharmaceuticals.
Gastrointestinal stromal tumors are mesenchymal tumors found in the gastrointestinal tract that originate from the interstitial cells of cajal, the pacemaker cells that regulate peristalsis in the digestive tract. Most gastrointestinal stromal tumors gists have activating mutations in the kit receptor tyrosine kinase, and most patients with gists respond well to gleevec, which inhibits kit kinase activity. Mutually exclusive kit and pdgfra mutations are central events in gist pathogenesis, and their understanding is becoming increasingly important, because specific treatment targeting oncogenic kit and pdgfra activation especially imatinib mesylate has become available. Thus, kit and pdgfra mutations appear to be alternative and mutually exclusive oncogenic mechanisms in. Gastrointestinal stromal tumors gists may be found anywhere in or near the gastrointestinal tract. A subset of gists, however, contains mutations in the homologous kinase platelet derived growth factor receptor alpha pdgfra, and the most common of these mutations is resistant. A gastrointestinal stromal tumor gist is a type of tumor that occurs in the gastrointestinal tract, most commonly in the stomach or small intestine.
Gastrointestinal stromal tumors gists are rare tumors, but are the most common primary mesenchymal tumor of the gastrointestinal tract 1. Pdgfra activating mutations in gastrointestinal stromal. Most mutations are somatic in tumor tissue only, but patients with familial gist syndrome have consitutitonal kit pdgfra mutations. Pdgfra mutations in gastrointestinal stromal tumors. These exons are mutation hotspots that account for the majority of pdgfra mutations detected in gastrointestinal stromal tumors gists including the common tkiresistance mutation d842v. Pdgfra exon 18 gastrointestinal stromal tumors gist michael heinrich,1 robin l. Mutant pdgfra has been implicated in the pathogenesis of a number of cancers. Less frequently, gist may arise in the appendix, gallbladder, pancreas, retroperitoneum, and paravaginal and periprostatic tissues. Gastrointestinal stromal tumors gists commonly harbor oncogenic mutations of the kit tyrosine kinase, which is a target for the kinase inhibitor imatinib. Fda approved ayvakit avapritinib for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor gist harboring a plateletderived growth factor receptor alpha. Imatinib, kit and pdgfra inhibitor, has been successfully used in the treatment of metastatic gists. Pdf gastrointestinal stromal tumors gists commonly harbor oncogenic mutations of the kit tyrosine kinase, which is a target for the kinase inhibitor. Pdgfra mutations in gastrointestinal stromal tumors ncbi.
In general, tumors with kit exon 11 mutations are most sensitive to imatinib, whereas gists harboring a mutation in pdgfra exon 18 p. The majority of gists associated with a mutation in the pdgfra gene occur in the stomach. Gastrointestinal stromal tumor gist, the most common mesenchymal neoplasm of the gastrointestinal tract, is resistant to conventional cytotoxic chemotherapy 1. Subtypes of kitpdgfra wildtype gastrointestinal stromal.
Pdgfra plateletderived growth factor receptor, alpha polypeptide encodes the plateletderived growth factor receptor alpha protein. Importance wildtype wt gastrointestinal stromal tumors gists, which lack kit and pdgfra gene mutations, are the primary form of gist in children and occasionally occur in adults. Despite clinicopathological differences, gists share oncogenic kit or platelet. Pitfalls in mutational testing and reporting of common kit. If cancerous, the tumor may also be called a soft tissue sarcoma. Dec 29, 2017 the life raft group provides medical information and builds an international support network for those with pediatric and wildtype gastrointestinal stromal tumors and funds research to find a cure for this cancer. On the basis of our findings and other cases of pdgfra mutant tumors published to date, the benefit of imatinib treatment may be limited for approximately 62. Gastrointestinal stromal tumors gists are the most common mesenchymal tumors of the gastrointestinal tract. Gastrointestinal stromal tumors gist are a type of soft tissue tumor that usually begin in specialized nerve cells in the wall of the stomach, intestines, or rectum, known as interstitial cells of cajal. Gastrointestinal stromal tumor genetics home reference nih. Mutational analysis of ckit or pdgfra has become an important laboratory assay for patients with gastrointestinal stromal tumors gists because the results are useful in predicting the responsiveness to imatinib. Kit pdgfra mutational assessment is important for decisionmaking and treatment purposes, as gastrointestinal gi stromal tumors gists have a variety of subtypes with different predictive and prognostic relevance. These tumors are made up of fibrous tissue and usually contain cells known to cause inflammation inflammatory cells.
This is a phase iii clinical trial of crenolanib in patients with advanced or metastatic gastrointestinal stromal tumors gist with a specific mutation d842v in the pdgfra gene. Kit and pdgfra mutations in gastrointestinal stromal tumors. In summary, we have surveyed the spectrum of pdgfra mutations found in gastrointestinal stromal tumors and examined their sensitivity to imatinib in vitro. This exploratory analysis of a randomized clinical trial investigates the effect of kit and pdgfra mutations on recurrencefree survival in a population of patients with gastrointestinal stromal tumors treated with surgery and adjuvant imatinib. Better molecular and clinical characterization could improve management. Gastrointestinal stromal tumours gists are the most common mesenchymal neoplasms of the gastrointestinal tract. In most cases, the genetic changes are acquired during a persons lifetime and are. Gastrointestinal stromal tumors gists are among a group of cancers known as sarcomas. Ebscohost serves thousands of libraries with premium essays, articles and other content including prognostic value of kitpdgfra mutations in gastrointestinal stromal tumours gist.
Approximately 80% of gists have a mutation in ckit and 5% to 10% of gists have a mutation in pdgfra. T1 pdgfra mutations in gastrointestinal stromal tumors. For example, mutations are found in gastrointestinal stromal tumors gist. Objective to evaluate the clinical and tumor genomic features of wt gist.
Gists express the tyrosine kinase receptor, kit, which is the protein product of the kit protooncogene. Kit and pdgfra mutations in gastrointestinal stromal tumors gists. Gastrointestinal stromal tumors genetic and rare diseases. In total, 85% of malignant gastrointestinal stromal tumours gists harbour activating mutations in one of the genes kit or pdgfra, while 10. Here we show that approximately 35% 14 of 40 of gists lacking kit mutations have intragenic activation mutations in the related receptor tyrosine. Differential expression of kitpdgfra mutant isoforms in. All gist cases with a mutation within pdgfra clustered on branch 2, together with two wildtype cases and two cases with mutations in kit exon. Jan 31, 2003 gastrointestinal stromal tumors gists are the most common mesenchymal tumors of the gastrointestinal tract and are particularly sensitive to gleevec, a new cancer therapy.
Gists are a type of tumor that occurs in the gastrointestinal tract, most commonly in the stomach or small intestine. Carneystratakis syndrome, an inherited condition predisposing affected individuals to gastrointestinal stromal tumor gist and paraganglioma, is caused by germline mutations in succinate dehydrogenase sdh subunits b, c, or d, leading to dysfunction of complex ii. Gastrointestinal stromal tumors nord national organization. Fda approves the first targeted therapy to treat a rare mutation in patients with gastrointestinal stromal tumors. Gastrointestinal stromal tumours gists are the most common type of mesenchymal tumours of the digestive tract, the majority of which 8287% are characterised by the presence of mutually exclusive gainoffunction mutations in pdgfra and kit 1, 46. Gastrointestinal stromal tumors gists are kit expressing spindle cell, epithelioid and rarely pleomorphic mesenchymal tumors. Frequency, spectrum and in vitro sensitivity to imatinib. Pdgfra activating mutations in gastrointestinal stromal tumors. Pathological characteristics of gastrointestinal stromal tumours with. May 17, 2004 gastrointestinal stromal tumors gists are kit expressing spindle cell, epithelioid and rarely pleomorphic mesenchymal tumors.
Heinrich will provide a background on the role of kinase mutations in gist, focusing largely on the biological and clinical implications of these mutations. Molecular characterization and pathogenesis of gastrointestinal. Mutations in the pdgfra gene are associated with gastrointestinal stromal tumors gists. The postulated relationship between kit pdgfra mutations and their prognostic value in gastrointestinal stromal tumors gists has generated intense attention during the past decade, despite the fact that a great deal of studies have been conducted on this subject.
Some gists are tiny about the size of a pencil eraser. Here we show that approximately 35% 14 of 40 of gists lacking kit mutations have intragenic activation mutations in the related receptor tyrosine kinase, plateletderived growth factor receptor alpha pdgfra. Pdgfra, plateletderived growth factor receptor alpha. Most mutations are somatic in tumor tissue only, but patients with familial gist syndrome have consitutitonal kitpdgfra mutations. A subset of gists, however, contains mutations in the homologous kinase platelet derived growth factor receptor alpha pdgfra, and the most common of these mutations is resistant to imatinib in vitro. Malignant examples of this tumor type were once viewed as the most treatmentrefractory sarcomas, with fewer than 10% of patients showing clinical response to conventional chemo or radiation therapies 1, 2.