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

Eileen Shi, Juliann Chmielecki, Chih Min Tang, Kai Wang, Michael Heinrich, Guhyun Kang, Christopher Corless, David Hong, Katherine E. Fero, James D. Murphy, Paul T. Fanta, Siraj M. Ali, Martina Siena, Adam M. Burgoyne, Sujana Movva, Lisa Madlensky, Gregory M. Heestand, Jonathan C. Trent, Razelle Kurzrock, Deborah MorosiniJeffrey S. Ross, Olivier Harismendy, Jason K. Sicklick

Research output: Contribution to journalArticle

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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

Original languageEnglish (US)
Article number339
JournalJournal of Translational Medicine
Volume14
Issue number1
DOIs
StatePublished - Dec 14 2016

Fingerprint

Gastrointestinal Stromal Tumors
Tumors
Genes
Gene Fusion
Fusion reactions
Neoplasms
Neoplasm Genes
Pediatrics
Lymph Nodes
Demography
Neoplasm Metastasis
Mutation
Therapeutics

Keywords

  • ETV6-NTRK3
  • FGFR1
  • Gene sequencing
  • GIST
  • Mutation

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors. / Shi, Eileen; Chmielecki, Juliann; Tang, Chih Min; Wang, Kai; Heinrich, Michael; Kang, Guhyun; Corless, Christopher; Hong, David; Fero, Katherine E.; Murphy, James D.; Fanta, Paul T.; Ali, Siraj M.; 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.

In: Journal of Translational Medicine, Vol. 14, No. 1, 339, 14.12.2016.

Research output: Contribution to journalArticle

Shi, E, Chmielecki, J, Tang, CM, Wang, K, Heinrich, M, Kang, G, Corless, C, Hong, D, Fero, KE, Murphy, JD, Fanta, PT, Ali, SM, Siena, M, Burgoyne, AM, Movva, S, Madlensky, L, Heestand, GM, Trent, JC, Kurzrock, R, Morosini, D, Ross, JS, Harismendy, O & Sicklick, JK 2016, 'FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors', Journal of Translational Medicine, vol. 14, no. 1, 339. https://doi.org/10.1186/s12967-016-1075-6
Shi, Eileen ; Chmielecki, Juliann ; Tang, Chih Min ; Wang, Kai ; Heinrich, Michael ; Kang, Guhyun ; Corless, Christopher ; Hong, David ; Fero, Katherine E. ; Murphy, James D. ; Fanta, Paul T. ; Ali, Siraj M. ; 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. / FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors. In: Journal of Translational Medicine. 2016 ; Vol. 14, No. 1.
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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

AU - Kang, Guhyun

AU - Corless, Christopher

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.

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. Registered October 12, 2015

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. Registered October 12, 2015

KW - ETV6-NTRK3

KW - FGFR1

KW - Gene sequencing

KW - GIST

KW - Mutation

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