Transcriptome analysis identifies ETV6-NTRK3 and PTCH1-GLI1 as novel gene fusions involved in Gastrointestinal Stromal Tumors and Myoepithelial Tumors

Gastrointestinal Stromal Tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. They feature, for the vast majority, KIT or PDGFRA mutations; less frequently BRAF, KRAS, PIK3CA, NF1 or SDH alterations. In about 10% of all GIST no distinct genetic alteration has been identified and this subset of tumors, defined as ‘quadruple negative GIST’, feature an overall poor response to standard treatments. In an attempt to better define ‘quadruple negative GIST’ pathobiology we investigate the possible involvement of fusion genes. RNA-sequencing followed by fusion gene analysis was performed in a series of 5 such tumors. Intriguingly, an ETV6-NTRK3 fusion was detected in one case. Stemming from our results, other GIST cases with the ETV6-NTRK3 fusion have been identified and included in a clinical trial with Larotrectinib, a novel drug targeting NTRK proteins, demonstrating a good response. Myoepithelial tumors (MyoT) are an uncommon heterogeneous group of tumors of uncertain differentiation. EWSR1, FUS or PLAG1 fusion genes (with different partners) and SMARCB1 deletions are genetic alterations already described in these tumors. A significant fraction of them still remain “orphan” of genetic marker due to the absence of known fusions. We performed RNA-sequencing and fusion gene detection in a series of 7 such tumors in order to identify novel fusion transcripts involved in their pathogenesis. Intriguingly one case turned out to express a PTCH1-GLI1 fusion that involved, respectively, the receptor and the nuclear effector of the Hedgehog (HH) pathway. This chimera worked as a hyperactive GLI1 allele by inducing HH canonical target genes and sustaining GLI1 autoregolatory loop. Finally, in an attempt to both dissect molecular diversity of MyoT and the closely related entity Extraskeletal Myxoid Chondrosarcoma (EMC) and to possible better define MyoT pathobiology, RNA-sequencing profiling was extended on a set of 12 EMC samples. Transcriptome profiles of the two entities were then compared. Overall, our results indicate that MyoT are a heterogeneous group of tumors that represent a distinct entity compared to EMC. Functional analysis with different bioinformatic tools suggested that, although heterogeneous, MyoT relied on common biologic signatures namely the activation of Hedgehog and WNT pathways.