Three novel concomitant NTRK2 fusions in medullary thyroid carcinoma with diagnostic implications

NTRK2 fusions are exceptionally rare but act as potent oncogenic drivers in diverse pediatric and adult cancers. Tumors harboring these fusions respond dramatically to TRK inhibitors (e.g., larotrectinib, entrectinib, and repotrectinib), which selectively target the constitutively active fusion protein. The identification of NTRK2 fusions has facilitated precision oncology approaches, significantly improving outcomes for patients with advanced cancers. Although specific NTRK2 fusion partners have been identified in thyroid cancer, NTRK2 fusions remain exceptionally rare and incompletely characterized in medullary thyroid carcinoma (MTC). In this case, three novel NTRK2 fusion transcript variants-GTF2I-NTRK2 (G9:N13), GTF2I-NTRK2 (G9:N14), and NTRK2-GTF2I (N12:G11)-co-occur in a 33-year-old woman with MTC. To our knowledge, all three fusion transcript variants are novel and previously unreported, and their co-occurrence in a single individual is particularly unusual. Targeted RNA sequencing results revealed three novel in-frame NTRK2 fusion transcript variants; two featured the same 5' partner sequences (exons 1-9) of the GTF2I gene fused to distinct NTRK2 3' sequences: one fusion contained the NTRK2 exons 13-19 sequences; the other contained the NTRK2 exons 14-19 sequences. The third in-frame fusion contained the 5' sequences (exons 1-12) of the NTRK2 gene fused to the 3' sequences (exons 11-35) of the GTF2I gene. The supporting reads for the fusion transcripts were systematically visualized using the Integrative Genomics Viewer (IGV) and validated by Sanger sequencing. Conclusively, this first report of three novel NTRK2 fusion transcript variants co-occurrence in an MTC patient expands the known spectrum of translocation partners in NTRK2 rearrangements. Prospective validation of their impact on TRK-targeted therapy efficacy and disease prognosis requires long-term follow-up.