Tropomyosin-Related Kinase Fusions in Gastrointestinal Stromal Tumors

Abstract

The canonical mutations in gastrointestinal stromal tumors (GISTs) are typically activating mutations in KIT and platelet-derived growth factor receptor alpha (PDGFRA). GISTs with non-canonical mutations are a heterogeneous group. Here, we examined tropomyosin-related kinase (TRK) fusion in GIST cases without KIT/PDGFRA mutations (KIT/PDGFRA wild-type (WT) GISTs). We retrospectively analyzed patients who were diagnosed with GISTs at the Yonsei Cancer Center, Severance Hospital, between January 1998 and December 2016. Thirty-one patients with KIT/PDGFRA WT GISTs were included in the analysis. TRK expression in tumor samples was assessed by pan-TRK immunohistochemistry (IHC), and the neurotrophic tyrosine receptor kinase (NTRK: the gene encoding TRK) rearrangement was analyzed by fluorescence in situ hybridization (FISH). IHC analyses revealed that five cases in this cohort exhibited a weak to moderate TRK expression. NTRK1 fusions were detected in three tumor samples, and two samples harbored NTRK3 fusions. The remaining 26 samples did not harbor NTRK fusions. Two types of NTRK fusions were detected, and the overall NTRK fusion frequency in KIT/PDGFRA WT GIST cases was 16% (5/31). Our data provide insights into the molecular alterations underpinning KIT/PDGFRA WT GISTs. More effort should be devoted to improve methods to identify this distinct disease subtype within the KIT/PDGFRA WT GIST group.

Keywords: KIT; PDGF receptor tyrosine kinase; gastrointestinal stromal tumor; neurotrophic tyrosine receptor kinase fusion; tropomyosin-related kinase fusion.

Figure 1

Representative images of pan-TRK expression in samples of WT GIST. IHC results showing samples in which the intensity of cytoplasmic staining was scored as negative (A), weakly positive (B), and moderately positive (C). There were no cases scored as strongly positive. Each scale bar is 100 μM. TRK: tropomyosin-related kinase; WT: wild type; GIST: gastrointestinal stromal tumor; IHC: immunohistochemistry.

Figure 2

Representative images of NTRK fusion detected by FISH. Tumor tissues were stained with dual-color FISH probes. The red and green signals represent upstream and downstream probes, respectively. FISH results showing (A) NTRK1 and (B) NTRK3 fusions. Each scale bar is 10 μM. Circles indicate gene rearrangements. NTRK: neurotrophic tyrosine receptor kinase; FISH: fluorescence in situ hybridization.