Genomic profiling of a DICER1-wildtype thyroblastoma reveals AGK-BRAF fusion, EIF1AX duplication, and TERT promoter mutations: integrated genomic and pathway analysis

Introduction Thyroblastoma is a rare and highly aggressive embryonal thyroid malignancy typically associated with DICER1 alterations. However, DICER1-wildtype cases remain poorly characterized at the molecular level. Methods We report a case of aggressive thyroblastoma in a 62-year-old male, negative for canonical DICER1 RNase IIIb mutations. Comprehensive genomic profiling was performed using Oxford Nanopore long-read sequencing, followed by integrative bioinformatic and pathway-level analyses. Results Molecular analysis revealed an alternative oncogenic signature characterized by an EIF1AX p.Lys3_Lys5dup duplication, TERT alterations (promoter C228T and coding p.C42R), and an AGK–BRAF fusion predicted to drive constitutive MAPK/ERK signaling. Functional enrichment analyses highlighted dysregulation of translational initiation, telomere maintenance, and mitogenic pathways, alongside potential immune-escape mechanisms linked to DUX4 activation. Clinically, the tumor exhibited a triphasic morphology, extensive locoregional infiltration, pulmonary metastases, and only transient response to chemotherapy. Discussion These findings expand the molecular spectrum of thyroblastoma beyond the canonical DICER1-driven paradigm and suggest that DICER1-wildtype cases may represent a distinct biological subgroup. The identification of alterations affecting TERT and MAPK pathways highlights potential therapeutic vulnerabilities and supports the clinical value of comprehensive genomic profiling in ultra-rare thyroid malignancies.