FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors.
| Title: | FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors. |
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| Authors: | Shi E; School of Medicine, University of California San Diego, La Jolla, CA, USA.; Chmielecki J; Foundation Medicine, Inc., Cambridge, MA, USA.; Tang CM; 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.; Wang K; Foundation Medicine, Inc., Cambridge, MA, USA.; Heinrich MC; Portland VA Health Care System, Portland, OR, USA.; Knight Cancer Institute, Oregon Health Sciences University, Portland, OR, USA.; Kang G; Knight Cancer Institute, Oregon Health Sciences University, Portland, OR, USA.; Department of Pathology, Sanggye Paik Hospital, Inje University, Seoul, Korea.; Corless CL; Knight Cancer Institute, Oregon Health Sciences University, Portland, OR, USA.; Hong D; Division of Cancer Medicine, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Fero KE; School of Medicine, University of California San Diego, La Jolla, CA, USA.; UCSD Department of Radiation Medicine and Applied Sciences, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.; Murphy JD; School of Medicine, University of California San Diego, La Jolla, CA, USA.; UCSD Department of Radiation Medicine and Applied Sciences, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.; Fanta PT; School of Medicine, University of California San Diego, La Jolla, CA, USA.; Division of Medical Oncology, Department of Medicine, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.; Ali SM; Foundation Medicine, Inc., Cambridge, MA, USA.; De Siena M; 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.; Burgoyne AM; School of Medicine, University of California San Diego, La Jolla, CA, USA.; Division of Medical Oncology, Department of Medicine, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.; Movva S; Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.; Madlensky L; School of Medicine, University of California San Diego, La Jolla, CA, USA.; UCSD Department of Family and Preventive Medicine, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.; Heestand GM; School of Medicine, University of California San Diego, La Jolla, CA, USA.; Division of Medical Oncology, Department of Medicine, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.; Trent JC; Sarcoma Medical Oncology Program, University of Miami Sylvester Cancer Center, Miami, FL, USA.; Kurzrock R; School of Medicine, University of California San Diego, La Jolla, CA, USA.; Division of Medical Oncology, Department of Medicine, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.; Morosini D; Foundation Medicine, Inc., Cambridge, MA, USA.; Ross JS; Foundation Medicine, Inc., Cambridge, MA, USA.; Harismendy O; School of Medicine, University of California San Diego, La Jolla, CA, USA. oharismendy@ucsd.edu.; 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. oharismendy@ucsd.edu.; Sicklick JK; School of Medicine, University of California San Diego, La Jolla, CA, USA. jsicklick@ucsd.edu.; 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. jsicklick@ucsd.edu. |
| Source: | Journal of translational medicine [J Transl Med] 2016 Dec 14; Vol. 14 (1), pp. 339. Date of Electronic Publication: 2016 Dec 14. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: BioMed Central Country of Publication: England NLM ID: 101190741 Publication Model: Electronic Cited Medium: Internet ISSN: 1479-5876 (Electronic) Linking ISSN: 14795876 NLM ISO Abbreviation: J Transl Med Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [London] : BioMed Central, 2003- |
| MeSH Terms: | Gastrointestinal Stromal Tumors/*metabolism ; Mutation/*genetics ; Receptor, Fibroblast Growth Factor, Type 1/*metabolism ; Receptor, trkC/*metabolism; Gastrointestinal Stromal Tumors/genetics ; Oncogene Proteins, Fusion/metabolism ; Adult ; Demography ; Female ; Genome, Human ; Humans ; Male |
| 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. |
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| Grant Information: | R21 CA192072 United States CA NCI NIH HHS; U54 HL108460 United States HL NHLBI NIH HHS; T32 HL086344 United States HL NHLBI NIH HHS; R21 CA177519 United States CA NCI NIH HHS; K08 CA168999 United States CA NCI NIH HHS; P30 CA023100 United States CA NCI NIH HHS; KL2 RR031978 United States RR NCRR NIH HHS; P30 CA006927 United States CA NCI NIH HHS; I01 BX000338 United States BX BLRD VA |
| Contributed Indexing: | Keywords: ETV6–NTRK3; FGFR1; GIST; Gene sequencing; Mutation |
| Molecular Sequence: | ClinicalTrials.gov NCT02576431 |
| Substance Nomenclature: | 0 (Oncogene Proteins, Fusion); EC 2.7.10.1 (FGFR1 protein, human); EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 1); EC 2.7.10.1 (Receptor, trkC) |
| Entry Date(s): | Date Created: 20161216 Date Completed: 20171016 Latest Revision: 20220331 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC5157084 |
| DOI: | 10.1186/s12967-016-1075-6 |
| PMID: | 27974047 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, Non-U.S. Gov't