EML4::RET, a novel transcript fusion in papillary thyroid cancer

Fusion genes are the most common genetic alterations found in pediatric papillary thyroid cancers (PTCs). Pediatric PTCs harboring fusion genes are generally associated with more aggressive disease than those without. RET (rearranged during transfection) rearrangements are the most common fusion genes in thyroid cancers. EML4 (human echinoderm microtubule-associated protein-like 4) was reported to be a fusion partner of ALK (anaplastic lymphoma kinase), NTRK (neurotrophic tyrosine receptor kinase), and MET (mesenchymal epithelial transition) fusion genes, but not of RET. We report a 16-year-old patient with PTC staged as pT3bN1bM1, who presented with lung metastases at diagnosis. RNA sequencing using our institution's next-generation sequencing panel revealed a novel EML4::RET transcript fusion. Between 2021 and 2024, the patient underwent 4 radioiodine (RAI) treatments for distant RAI-avid metastases, with remarkable response on posttherapeutic whole-body scans and by declining serum thyroglobulin levels. EML4::RET transcript fusion needs to be recognized as a novel rearrangement in PTC.