Approximately 10–20% of thyroid cancers are driven by gene fusions, which activate oncogenic signaling through aberrant overexpression, ligand-independent dimerization or loss of inhibitory motifs. We identified 13 thyroid tumors with thyroglobulin (TG) gene fusions and aimed to assess their histopathology and the fusions’ oncogenic and tumorigenic properties. Of eleven cases with surgical pathology, 82% were carcinomas and 18% were noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP). TG fusions preserved exon(s) 1, 1–15, 1–35 or most frequently, 1–47 of TG and, based on the 3′ partner were grouped as i) involving receptor tyrosine kinases (RTKs) (TG::FGFR1, TG::RET, TG::ALK and TG::NTRK1), ii) driving aberrant DPRX and chromosome 19 microRNA cluster expression (TG::DPRX) or iii) involving IGF2 mRNA-binding protein (TG::IGF2BP1). All 13 fusion-positive tumors exhibited strong (8.5 ± 3.3 log2-fold) 3′ partner overexpression driven by the TG promoter. Gene expression analysis revealed TG::RET- and TG::ALK-positive tumors being BRAFV600E-like and remaining tumors RAS-like. In thyroid PCCL3 cells, the TG::NTRK1 fusion demonstrated both spontaneous and ligand-associated dimerization, activated downstream MAPK, AKT and STAT3 signaling and drove xenograft tumorigenesis in nude mice. FDA-approved NTRK inhibitors entrectinib and larotrectinib effectively blocked TG::NTRK1 signaling in vitro and inhibited xenograft tumor growth in vivo. In summary, we report a spectrum of TG gene fusions as recurrent oncogenic events in thyroid cancer and NIFTP that drive strong overexpression of partner genes, frequently RTKs. The TG::NTRK1 fusion is prone to dimerization, activates oncogenic signaling, drives tumorigenesis in thyroid cells and, like other fusions involving RTKs, represents a potential therapeutic target in thyroid cancer.
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