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Shi E , Chmielecki J , Tang CM , Wang K , Heinrich MC , Kang G , Corless CL , Hong D , Fero KE , Murphy JD , Fanta PT , Ali SM , De Siena M , Burgoyne AM , Movva S , Madlensky L , Heestand GM , Trent JC , Kurzrock R , Morosini D , Ross JS , Harismendy O , Sicklick JK
FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors
J Transl Med. 2016 Dec 14;14(1) :339
PMID: 27974047    PMCID: PMC5157084   
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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.
1479-5876 Shi, Eileen Chmielecki, Juliann Tang, Chih-Min Wang, Kai Heinrich, Michael C Kang, Guhyun Corless, Christopher L Hong, David Fero, Katherine E Murphy, James D Fanta, Paul T Ali, Siraj M De Siena, Martina Burgoyne, Adam M Movva, Sujana Madlensky, Lisa Heestand, Gregory M Trent, Jonathan C Kurzrock, Razelle Morosini, Deborah Ross, Jeffrey S Harismendy, Olivier Sicklick, Jason K R21 CA192072/CA/NCI NIH HHS/United States U54 HL108460/HL/NHLBI NIH HHS/United States T32 HL086344/HL/NHLBI NIH HHS/United States R21 CA177519/CA/NCI NIH HHS/United States K08 CA168999/CA/NCI NIH HHS/United States P30 CA023100/CA/NCI NIH HHS/United States KL2 RR031978/RR/NCRR NIH HHS/United States I01 BX000338/BX/BLRD VA/United States Journal Article England J Transl Med. 2016 Dec 14;14(1):339.