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

Abstract

BackgroundAbout 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.MethodsWe performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations.ResultsWe 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.ConclusionsUsing 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, 2015Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1075-6) contains supplementary material, which is available to authorized users.

A NovelPRKAR1B-BRAFFusion in Gastrointestinal Stromal Tumor Guides Adjuvant Treatment Decision-Making During Pregnancy

“…Recently, we and others reported a handful of gene fusions in GIST 4–7 (Table 1). However, here we report a novel, previously unreported PRKAR1B-BRAF gene fusion in a patient with GIST (Figure 2).…”

“…3 We and others recently reported that a small subset of GISTs also occur due to kinase fusions (eg, ETV6-NTRK3 , FGFR1-TACC1 , FGFR1-HOOK3 ), a previously unappreciated mechanism for GIST tumorigenesis. 4–7 …”

Biochemical, Molecular, and Clinical Characterization of Succinate Dehydrogenase Subunit A Variants of Unknown Significance

“…We gathered SDHA VUS from two primary sources: The OHSU Knight Diagnostics Laboratory (Portland, OR) and the literature(12,13). The majority of the variants pulled from the literature were found in a review highlighting the need for a functional model to characterize SDHx variants of unknown significance (12).…”

“…The majority of the variants pulled from the literature were found in a review highlighting the need for a functional model to characterize SDHx variants of unknown significance (12). The remaining literature variants are from a paper identifying novel causes of GIST that were WT for any known oncogenic driver of GIST (13). A collaboration with the OHSU Knight Diagnostics Laboratory, which offers a targeted exome panel to identify genetic drivers in GIST which includes all four SDHx subunits (https://www.ohsu.edu/custom/knight-diagnostic-labs/home/test-details?id=GeneTrails+GIST+Genotyping+Panel), lead to identification of several novel variants.…”

“…A universal problem in the field is that these variants are rarely seen with a complete clinical and pathogenic annotation making it difficult to draw conclusions on functional effect from clinical data alone. Our study gathered these VUS from two primary sources; OHSU and the literature (12,13). We then combine data from clinical observations, a functional yeast model, and a computational model to understand the effects of SDHA VUS identified in GIST specimens on SDH complex function.…”