title: FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: School of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Shi
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Juliann
authors.initials: J
authors.lastname: Chmielecki
authors.affiliation: 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.
authors.forename: Chih-Min
authors.initials: CM
authors.lastname: Tang
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Portland VA Health Care System, Portland, OR, USA.|Knight Cancer Institute, Oregon Health Sciences University, Portland, OR, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.affiliation: Knight Cancer Institute, Oregon Health Sciences University, Portland, OR, USA.|Department of Pathology, Sanggye Paik Hospital, Inje University, Seoul, Korea.
authors.forename: Guhyun
authors.initials: G
authors.lastname: Kang
authors.affiliation: Knight Cancer Institute, Oregon Health Sciences University, Portland, OR, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.affiliation: Division of Cancer Medicine, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.affiliation: 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.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Fero
authors.affiliation: 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.
authors.forename: James D
authors.initials: JD
authors.lastname: Murphy
authors.affiliation: 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.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Fanta
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: 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.
authors.forename: Martina
authors.initials: M
authors.lastname: De Siena
authors.affiliation: 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.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Burgoyne
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Sujana
authors.initials: S
authors.lastname: Movva
authors.affiliation: 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.
authors.forename: Lisa
authors.initials: L
authors.lastname: Madlensky
authors.affiliation: 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.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Heestand
authors.affiliation: Sarcoma Medical Oncology Program, University of Miami Sylvester Cancer Center, Miami, FL, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Trent
authors.affiliation: 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.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Morosini
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Harismendy
authors.affiliation: 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.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Sicklick
mesh_terms: D000328:Adult; D003710:Demography; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism*; D015894:Genome, Human; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D020812:Receptor, trkC / Q000378:metabolism*
chemical_list: D015514:Oncogene Proteins, Fusion; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020812:Receptor, trkC
keywords: ETV6–NTRK3; FGFR1; GIST; Gene sequencing; Mutation