TY - JOUR
T1 - FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors
AU - Shi, Eileen
AU - Chmielecki, Juliann
AU - Tang, Chih Min
AU - Wang, Kai
AU - Heinrich, Michael C.
AU - Kang, Guhyun
AU - Corless, Christopher L.
AU - Hong, David
AU - Fero, Katherine E.
AU - Murphy, James D.
AU - Fanta, Paul T.
AU - Ali, Siraj M.
AU - Siena, Martina
AU - Burgoyne, Adam M.
AU - Movva, Sujana
AU - Madlensky, Lisa
AU - Heestand, Gregory M.
AU - Trent, Jonathan C.
AU - Kurzrock, Razelle
AU - Morosini, Deborah
AU - Ross, Jeffrey S.
AU - Harismendy, Olivier
AU - Sicklick, Jason K.
N1 - Publisher Copyright:
© 2016 The Author(s).
PY - 2016/12/14
Y1 - 2016/12/14
N2 - 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.
AB - 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.
KW - ETV6-NTRK3
KW - FGFR1
KW - GIST
KW - Gene sequencing
KW - Mutation
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U2 - 10.1186/s12967-016-1075-6
DO - 10.1186/s12967-016-1075-6
M3 - Article
C2 - 27974047
AN - SCOPUS:85005987227
SN - 1479-5876
VL - 14
JO - Journal of translational medicine
JF - Journal of translational medicine
IS - 1
M1 - 339
ER -