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      FGFR1 and NTRK3 actionable alterations in “Wild-Type” gastrointestinal stromal tumors

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          Abstract

          Background

          About 10–15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies.

          Methods

          We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations.

          Results

          We identified 24 GIST lacking alterations in the canonical KIT/PDGFRA/RAS pathways, including 12 without SDHx alterations. These 24 patients were mostly adults (96%). The tumors had a 46% rate of nodal metastases. These 24 GIST were more commonly mutated at 7 genes: ARID1B, ATR, FGFR1, LTK, SUFU, PARK2 and ZNF217. Two tumors harbored FGFR1 gene fusions (FGFR1–HOOK3, FGFR1–TACC1) and one harbored an ETV6–NTRK3 fusion that responded to TRK inhibition. In an independent sample set, we identified 5 GIST cases lacking alterations in the KIT/PDGFRA/SDHx/RAS pathways, including two additional cases with FGFR1–TACC1 and ETV6–NTRK3 fusions.

          Conclusions

          Using patient demographics, tumor characteristics, and CGP, we show that GIST lacking alterations in canonical genes occur in younger patients, frequently metastasize to lymph nodes, and most contain deleterious genomic alterations, including gene fusions involving FGFR1 and NTRK3. If confirmed in larger series, routine testing for these translocations may be indicated for this subset of GIST. Moreover, these findings can be used to guide personalized treatments for patients with GIST.

          Trial registration NCT 02576431. Registered October 12, 2015

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12967-016-1075-6) contains supplementary material, which is available to authorized users.

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          Most cited references 28

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          Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family.

          In mammals, fibroblast growth factors (FGFs) are encoded by 22 genes. FGFs bind and activate alternatively spliced forms of four tyrosine kinase FGF receptors (FGFRs 1-4). The spatial and temporal expression patterns of FGFs and FGFRs and the ability of specific ligand-receptor pairs to actively signal are important factors regulating FGF activity in a variety of biological processes. FGF signaling activity is regulated by the binding specificity of ligands and receptors and is modulated by extrinsic cofactors such as heparan sulfate proteoglycans. In previous studies, we have engineered BaF3 cell lines to express the seven principal FGFRs and used these cell lines to determine the receptor binding specificity of FGFs 1-9 by using relative mitogenic activity as the readout. Here we have extended these semiquantitative studies to assess the receptor binding specificity of the remaining FGFs 10-23. This study completes the mitogenesis-based comparison of receptor specificity of the entire FGF family under standard conditions and should help in interpreting and predicting in vivo biological activity.
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            Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic.

            Wild-type (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. They respond poorly to standard targeted therapy. Better molecular and clinical characterization could improve management.
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              BCoR, a novel corepressor involved in BCL-6 repression.

              BCL-6 encodes a POZ/zinc finger transcriptional repressor that is required for germinal center formation and may influence apoptosis. Aberrant expression of BCL-6 due to chromosomal translocations is implicated in certain subtypes of non-Hodgkin's lymphoma. The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT. Here we identify and characterize a novel corepressor BCoR (BCL-6 interacting corepressor), which is expressed ubiquitously in human tissues. BCoR can function as a corepressor when tethered to DNA and, when overexpressed, can potentiate BCL-6 repression. Specific class I and II histone deacetylases (HDACs) interact in vivo with BCoR, suggesting that BCoR may functionally link these two classes of HDACs. Strikingly, BCoR interacts selectively with the POZ domain of BCL-6 but not with eight other POZ proteins tested, including PLZF. Additionally, interactions between the BCL-6 POZ domain and SMRT, N-CoR, and BCoR are mutually exclusive. The specificity of the BCL-6/BCoR interaction suggests that BCoR may have a role in BCL-6-associated lymphomas.
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                Author and article information

                Contributors
                eishi@ucsd.edu
                Juliann.chmielecki@gmail.com
                cmtang@ucsd.edu
                kwang@foundationmedicine.com
                heinrich@ohsu.edu
                gkang@paik.ac.kr
                corlessc@ohsu.edu
                dshong@mdanderson.org
                kfero@mail.ucsd.edu
                j2murphy@ucsd.edu
                pfanta@ucsd.edu
                sali@foundationmedicine.com
                mdesiena@ucsd.edu
                aburgoyne@ucsd.edu
                sujana.movva@fccc.edu
                lmadlensky@ucsd.edu
                gheestand@AD.UCSD.EDU
                jtrent@med.miami.edu
                rkurzrock@ucsd.edu
                deborah@loxooncology.com
                rossj@mail.amc.edu
                (858) 246-0248 , oharismendy@ucsd.edu
                858-822-3967 , jsicklick@ucsd.edu
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                1479-5876
                14 December 2016
                14 December 2016
                2016
                : 14
                Affiliations
                [1 ]School of Medicine, University of California San Diego, La Jolla, CA USA
                [2 ]Foundation Medicine, Inc., Cambridge, MA USA
                [3 ]Oncogenomics Laboratory, Division of Biomedical Informatics, Moores UCSD Cancer Center, UC San Diego Health Sciences, University of California San Diego, 3855 Health Sciences Drive, Room 4335, Mail Code 0820, La Jolla, CA 92093-0820 USA
                [4 ]Portland VA Health Care System, Portland, OR USA
                [5 ]Knight Cancer Institute, Oregon Health Sciences University, Portland, OR USA
                [6 ]Department of Pathology, Sanggye Paik Hospital, Inje University, Seoul, Korea
                [7 ]Division of Cancer Medicine, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX USA
                [8 ]UCSD Department of Radiation Medicine and Applied Sciences, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA USA
                [9 ]Division of Medical Oncology, Department of Medicine, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA USA
                [10 ]Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA USA
                [11 ]UCSD Department of Family and Preventive Medicine, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA USA
                [12 ]Sarcoma Medical Oncology Program, University of Miami Sylvester Cancer Center, Miami, FL USA
                [13 ]Division of Surgical Oncology, Department of Surgery, Moores UCSD Cancer Center, UC San Diego Health Sciences, University of California San Diego, 3855 Health Sciences Drive, Room 2313, Mail Code 0987, La Jolla, CA 92093-0987 USA
                Article
                1075
                10.1186/s12967-016-1075-6
                5157084
                27974047
                © The Author(s) 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: KL2 RR031978
                Award ID: R21 CA 177519
                Award ID: R21 CA192072
                Award ID: P30 CA023100
                Award ID: U54 HL108460
                Award ID: K08 CA168999
                Award ID: R21 CA192072
                Award ID: P30 CA023100
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000738, U.S. Department of Veterans Affairs;
                Award ID: 1I01BX000338-01
                Award ID: 2I01BX000338-05
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Medicine

                gene sequencing, mutation, gist, fgfr1, etv6–ntrk3

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