Secondly that, although supported by different mechanisms an autocrineparacrine activation loop of pdgfra, pdgfrb and kit in chordoma tamborini et. It occurs when a mutation on chromosome 4 causes deletion of approximately 800 nucleotides, or dna building blocks, which normally separate the fip1l1 and pdgfra genes. The fda has approved avapritinib for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor who harbor plateletderived growth factor receptor alpha exon 18 mutation, including pdgfra d842v mutations. Pdgfra mutations as a diagnostic biomarker in gist. Lung cancer prostate cancer skin cancer all cancer types. We use cookies to enhance the usability of our website.
Evidence for pdgfra, pdgfrb and kit deregulation in an nsclc. Sep 26, 2014 crenolanib, a pdgfr inhibitor, suppresses lung cancer cell proliferation and inhibits tumor growth in vivo ping wang, 1 liqiang song, 2 hui ge, 1 pule jin, 1 yifang jiang, 1 wenxia hu, 1 and nan geng 1. Use of ckitpdgfra mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumors entered on phase i and ii studies of the eortc soft tissue and bone sarcoma group. Vandetanib versus placebo in patients with advanced nonsmallcell lung cancer after prior therapy with an epidermal growth factor receptor. Ayvakit approved to treat gist with pdgfra exon 18 mutation. The majority of gists associated with a mutation in the pdgfra gene occur in the stomach. Clinical and translational implications of ret rearrangements. A pdgfr exon 18 mutation creates a lock that none of our previous keys fit into, he explained. Pdgfra cosmic, sanger institute somatic mutation information and related details. Pdgfra gene rearrangements are frequent genetic events in. Tumor cell pdgfra expression in lung cancer xenografts.
The most common alterations in pdgfra are pdgfra mutation 3. Expression of pdgfra cd140a, gas9, pdgfr2 in cancer tissue. An immunohistochemical and molecular genetic analysis of kit and. Their pdgfra mutation frequency was higher than that in our cohort, which may be due to the fact that whole exons were sequenced, whereas we only sequenced the mutation hotspot of pdgfra. The spectrum of activity of crenolanib suggests that this drug is a type i inhibitor inhibitor of activated conformation of kinase. Like many receptor tyrosine kinases rtks, pdgfra is involved in the progression of a variety of cancers, such as leukemias, gastrointestinal stromal tumors gists, glioblastoma, and hepatocellular carcinoma, either by overexpression or by increased activity due, for example, to mutation or chromosomal rearrangement. On january 9, 2020, the fda approved avapritinib for adults with unresectable or metastatic gist harboring a pdgfra exon 18 mutation, including the pdgfra d842v alteration, the most common exon 18.
Pdgfra plateletderived growth factor receptor, alpha. These cells help fight infections by certain parasites and are involved in the inflammation associated with allergic reactions. Limited series in glioblastoma, lung cancer, and malignant peripheral nerve sheath tumor identified 4q12amp by fluorescence in situ hybridization or immunohistochemistry. Neomorphic pdgfra extracellular domain driver mutations.
A better understanding of its biological behaviour is warranted to define more accurate prognosis and therapeutic targets. However, previous studies have shown that patients with a pdgfra d842v mutation in gists have a. The fip1lipdgfra gene sequence is one of those genetic changes acquired after birth. Pdgfra mutations in gastrointestinal stromal tumors. Gastrointestinal stromal tumors treatment adult pdq. Nonsmall cell lung carcinomas have a poor response to conventional chemotherapy. We investigated the pdgfra locus in pdgfraamplified gliomas and identified two. The stage is categorized by how far the lung cancer has spread from its original site. Jan 01, 2010 we also found that the sites of mutation in ckit and pdgfra correlated with specific anatomic sites, as previously described in the literature. When the fip1l1pdgfra fusion gene mutation or point mutations in the pdgfra gene occur in early blood cells, the growth of eosinophils and occasionally other blood cells is poorly controlled, leading to pdgfraassociated chronic eosinophilic leukemia.
An update of driver mutations, their role in pathogenesis and clinical significance robert c. Mutations in the pdgfra gene are associated with gastrointestinal stromal tumors gists. Mutation analysis should be performed using an appropriate, validated, technique, and performed by specifically trained personnel and results should always specify the type of analysis performed, the region or mutations evaluated, and the sensitivity of the detection method used 18. Globally, about % of all new cancers are lung cancers. This work was supported by the nci spore in lung cancer award p20 ca09057806. Molecular analysis performed for investigating the mutation hotspots of. Our findings suggest that in additional rare cases of nsclc and sarcoma pdgfra activation may be important in maintaining the. Not all of these mutations are susceptible to existing kinase inhibitors, and many inhibitors are nonspecific, resulting in undesirable offtarget effects. To all detected genes, 11 cases 1122, 50% of lung mcrc and 11 cases 1120, 55% of liver. We selected 16 pdgfra mutations which have not been studied or characterized from the tcga, genie, or identified in md anderson cancer center. Get detailed information about the diagnosis, prognosis, and treatment of newly diagnosed and recurrent gist in this summary for clinicians. Jan 09, 2020 the fda has approved avapritinib for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor who harbor plateletderived growth factor receptor alpha exon 18 mutation, including pdgfra d842v mutations. The coamplification of three distinct rtk encoding geneskit, kdr, and pdgfraon chromosome 4q12 4q12amp may similarly be an oncogenic driver and thus target for therapy.
In vitro, apatinib did not suppress viability of kif5brettransfected a549 lung cancer cell lines. Expression of pdgfra in colorectal cancer the human protein. Adenosquamous carcinoma of the uterine cervix is an infrequent but aggressive subtype of cervical cancer. Fathmmmkl is an algorithm which predicts the functional, molecular and phenotypic consequences of protein missense variants using hidden markov models. Pdgfra mutations are frequently observed in patients with gastrointestinal stromal tumors gist. Pdgfraassociated chronic eosinophilic leukemia is a form of blood cell cancer characterized by an elevated number of cells called eosinophils in the blood. Arog pharmaceuticals receives fda fast track designation for crenolanib for advanced gastrointestinal stromal tumors with a d842v mutation in the pdgfra gene. Arog pharmaceuticals receives fda fast track designation. In laboratory studies, the drug could bind to all tested mutant pdgfra proteins and inhibit their activity in cancer cells. Pdgfra geo profiles, ncbi search the gene expression profiles from curated datasets in the gene expression omnibus geo repository. Previous reports of pdgfra activation in cancer have been largely confined to gists activating pdgfra mutations and rare cases of idiopathic hypereosinophilic syndrome fip1l1 pdgfra fusion transcripts 18, 19. The mutation impact filters are derived from the fathmmmkl algorithm functional analysis through hidden markov models. Kras mutations in lung cancer appear to be mutually exclusive with egfr mutations and with alk translocations and are more often associated with patients with a smoking history.
Summary of gene and mutations by cancer type from icgc. Sequence analysis of the entire coding sequence of pdgfra, pdgfrb and ckit in this cell line revealed a single mutation in exon 9 of pdgfra s478p. Gists are a type of tumor that occurs in the gastrointestinal tract, most commonly in the stomach or small intestine. Crenolanib inhibits the drugresistant pdgfra d842v mutation. Secondary pdgfra mutations have been identified in exon 18, generally accompanied by a primary mutation in same gene 17. Pdgfra d842v mutation has been found in a distinct subset of gist, typically from the stomach. Egfr mutation testing is used primarily to help guide treatment and determine whether someone with nonsmall cell lung cancer nsclc may benefit from targeted therapy such as with the tyrosine kinase inhibitors tkis gefitinib and erlotinib. The kinase inhibitor ayvakit avapritinib has been approved to treat adults with unresectable or metastatic gastrointestinal stromal tumors gists with a plateletderived growth factor receptor alpha pdgfra exon 18 mutation, the u.
Jan 31, 2020 gastrointestinal stromal tumors gists are the most common type of adult mesenchymal neoplasms. Avapritinib was chosen for development specifically based on its ability to bind to pdgfra and kit proteins. The cancer tissue page shows antibody staining of the protein in 20 different cancers. Five lung cancer cases with longitudinal ctdna sampling were monitored for cancer progression or response to treatments. A diagnosis of lung cancer is usually confirmed by examining tissue andor cells from the lungs with a microscope.
The food and drug administration has approved avapritinib ayvakit for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumors gist with a plateletderived growth factor receptoralpha pdgfra exon 18 mutation. Alk expressed in a gastrointestinal stromal tumor harboring. The invitae common hereditary cancers panel includes genes that increase risk for each of these types of gastric tumors. Plateletderived growth factor signaling in the lung. To identify mutations in plateletderived growth factor receptor alpha pdgfra gene seen in a subset of gastrointestinal stromal tumors gist which can help confirm the diagnosis of gist and are useful for therapeutic planning. Humera khurshid, md abstract lung cancer is the most common malignancy in the us and causes the most cancer related deaths. This approval makes avapritinib the first precision medicine therapy for a genomically defined population of patients with gist, according to a press release from. Pdgfra gene rearrangement in these tumors is unknown. Kras is one of the most frequently mutated genes in lung cancer, occurring in 25% of adenocarcinomas.
Sep 15, 2015 libraries were prepared using the ion ampliseq library kit 2. However, these circumstances do not account for the increased number of eosinophils in pdgfra. Based in part on these results, a phase ii clinical study of this agent to treat gist with the pdgfra d842v mutation has been. Aberrant activation of this pathway by mutations of any member is known to appear in several types of human cancer. Based in part on these results, a phase ii clinical study of this agent to treat gist with the pdgfra d842v mutation has been initiated. Pdgfraassociated chronic eosinophilic leukemia genetics. Fda approves avapritinib for adults with gist with pdgfra. However, the incidence of plateletderived growth factor receptor.
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. Kit cd117 expression is detected immunohistochemically in 95% of gists, making it a key diagnostic marker, together with anoctamin1 dog1 18. Predictive and prognostic value of phosphorylated ckit and. On january 9, the food and drug administration fda approved avapritinib ayvakit for some adults with gist whose tumors have an alteration in a portion of the pdgfra gene called exon 18. The most common of these alterations is called a d842v mutation. In most cases, the genetic changes are acquired during a persons lifetime and are called somatic.
Expression of pdgfra in colorectal cancer the human. In 5 to 6% of unresectable or metastatic gist patients, an activation loop mutation in pdgfra at amino acid 842 occurs as the primary mutation 14, 15 and is insensitive to imatinib and all other approved gist agents 16, 17. Pdgfra y288c expression enhances malignant phenotypes. Avapritinib approved for gist with pdgfra gene alteration. Avapritinib is a game changer for pdgfra exon 18mutated gist. When the fip1l1 pdgfra fusion gene mutation or point mutations in the pdgfra gene occur in early blood cells, the growth of eosinophils and occasionally other blood cells is poorly controlled, leading to pdgfra associated chronic eosinophilic leukemia. Pdgfra gene, drug resistance, tissue distribution, mutation distribution, variants, pdgfra genome browser, pdgfra references. Activating mutation in genes encoding critical signaling molecules has been identified in patients with different types of tumors, including nsclc.
All coding exons of pdgfra were sequenced by direct sequencing of pcramplified products from genomic dna in the tumors listed in the supplementary table s2, including 39 cases of nonbrainstem pediatric hggs and 43 cases of dipgs, using primers listed in the supplementary table s4, or by exome sequencing for three dipg samples. Gastrointestinal stromal tumor gist treatment depends on the extent of disease and may involve surgery andor tyrosine kinase inhibitors. Evidence for pdgfra, pdgfrb and kit deregulation in an. Constitutive activation of pdgfr signaling, gene rearrangement, and activating mutations of pdgfr have been identified in various types of. If the tissue or cells are cancerous, the next step is to determine the stage or extent of disease. Previous reports of pdgfra activation in cancer have been largely confined to gists. Pdgfra mutation analysis md anderson cancer center. Stromal plateletderived growth factor receptor a pdgfra. The most common pdgfra mutation occurs at a rate of 62 percent and involves exon 18, loci for the receptors activation loop.
It is unclear why eosinophils are preferentially affected by this genetic change. Nonsmall cell lung carcinomas most frequently harbor alterations in tp53, kras, egfr, cdkn2a, and stk11. In about 5% to 10% of gists, the cancer cells have a mutation in the pdgfra gene, which causes the cells to make too much of the pdgfra protein. Cstone submits ayvakit for approval in taiwan for pdgfra. In addition, the cases in the tcga database were most likely. Avapritinib approved by the fda for treatment of pdgfra 18. Pdgfra explore an overview of pdgfra, with a histogram displaying coding mutations, full tabulated details of all associated variants, tissue distribution and any drug resistance data. This approval makes avapritinib the first precision medicine therapy for a genomically defined population of patients with gist, according to a press.
Gastrointestinal stromal tumors gists are the most common type of adult mesenchymal neoplasms. Kras mutations in lung cancer localize primarily to codons 12 and. Mar 14, 2020 on january 9, 2020, the fda approved avapritinib for adults with unresectable or metastatic gist harboring a pdgfra exon 18 mutation, including the pdgfra d842v alteration, the most common exon 18. Pdgfra associated chronic eosinophilic leukemia is a form of blood cell cancer characterized by an elevated number of cells called eosinophils in the blood. Because of this deletion, the two genes are brought together, producing a new fusion gene. Srp provides national leadership in the science of cancer surveillance as well as analytical tools and methodological expertise in collecting, analyzing, interpreting, and disseminating reliable populationbased. The events that drive gist oncogenesis are primarily kit or pdgfra mutations, which lead to the susceptibility of these tumors to smallmolecule tyrosine kinase inhibitors such as imatinib and sunitinib. The d842v mutation results in an amino acid substitution at position 842 in pdgfra, from an aspartic acid d to a valine v. May 01, 2009 previous reports of pdgfra activation in cancer have been largely confined to gists activating pdgfra mutations and rare cases of idiopathic hypereosinophilic syndrome fip1l1 pdgfra fusion transcripts 18, 19.
However, previous studies have shown that patients with a pdgfra d842v mutation in. Seer is supported by the surveillance research program srp in ncis division of cancer control and population sciences dccps. Crenolanib, a pdgfr inhibitor, suppresses lung cancer cell proliferation and inhibits tumor growth in vivo. Nonsmallcell lung carcinoma nsclc accounts for the majority of cases. Neomorphic pdgfra extracellular domain driver mutations are. If you continue, well assume that you are happy to receive all cookies. Gene rearrangement in the form of an intragenic deletion is the primary mechanism of oncogenic mutation of the epidermal growth factor receptor egfr gene in gliomas. Jan 10, 2020 the food and drug administration has approved avapritinib ayvakit for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumors gist with a plateletderived growth factor receptoralpha pdgfra exon 18 mutation.
Bidirectional sequencing of exons 12 and 18 of the pdgfra plateletderived growth factor alpha gene. People with gastrointestinal stromal tumors gist driven by a specific gene alteration have a new targeted drug option for treatment. Mutations in receptor tyrosine kinases are common in cancer, and a variety of kinase mutations can have oncogenic effects. In 5 to 6% of unresectable or metastatic gist patients, an activation loop mutation in pdgfra at amino acid 842 occurs as the primary mutation 14, 15 and is insensitive to imatinib and all other approved gist agents. Secondly that, although supported by different mechanisms an autocrineparacrine activation loop of pdgfra, pdgfrb and kit in chordoma tamborini et al, 2006 and a gene gain in lung cancer, the. Libraries were prepared using the ion ampliseq library kit 2. It is intended as a resource to inform and assist clinicians who care for cancer patients. Crenolanib, a pdgfr inhibitor, suppresses lung cancer cell. Clinical and translational implications of ret rearrangements in nonsmall cell. The lung carcinoma was initially surgically treated, but relapsed to. The aggressiveness of a lung cancer tumour and the risk of it spreading have been linked to a gene mutation, the daily telegraph reported. The discovery of this gene could lead to the development of a test that would allow doctors to treat the disease more effectively, and patients could be given varying doses of chemotherapy drugs depending on which form of the gene they had the. This pdgfra mutantsimilar to the kit mutantresults in a constitutively active. A group of at least three distinct histological types of lung cancer, including nonsmall cell squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.
The fip1li pdgfra gene sequence is one of those genetic changes acquired after birth. Crenolanib inhibits the drugresistant pdgfra d842v. Ret mutation and expression in smallcell lung cancer. This mutation occurs within the tk2 domain figure 1. Cancer landscape of coamplification of the tyrosine. In this study, we consistently detected a homozygous silent mutation in exon 12 of pdgfra, involving a single point mutation of adenine to guanine at nucleotide 1849. Largescale analysis of pdgfra mutations in melanomas and. Currently, the blockage of receptor tyrosine kinase rtks activity is an efficient therapeutic strategy for many different cancers.
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