Somatic mutations in the TG and RELA genes specific for radioiodine-refractory thyroid cancer.

Radioactive iodine-refractory (RAI-R) thyroid cancer is associated with poor prognosis and limited treatment options. Identifying RAI-R status early in treatment is crucial for optimizing therapy. This study aims to identify genetic variants distinguishing RAI-R from radioiodine-sensitive (RAI-S) thyroid cancers. The study included six RAI-R patients and six age-matched RAI-S controls. DNA from tumor tissues and peripheral leukocytes of RAI-R patients underwent long-read whole-genome sequencing, while tumor DNA from RAI-S patients underwent whole-exome sequencing. RNA and immunohistochemistry (IHC) analyses were performed to assess candidate variants. Among the six RAI-R patients, three showed disease progression. These patients harbored somatic heterozygous variants in the TG gene, including a c.7863-7_7864delTTCTCACinsG variant, an 8,232 bp deletion encompassing exons 33-34, and a missense variant (c.5488 C > T; p.Pro1830Ser). No TG variants were found in RAI-S or non-progressive RAI-R patients. Additionally, one RAI-R patient had a somatic nonsense variant in the RELA gene (c.601 C > T; p.Arg201Ter). qRT-PCR showed lower NIS expression in RAI-R patients with TG or RELA variants, whereas RAI-S patients exhibited higher NIS expression. Somatic TG and RELA variants were identified in RAI-R thyroid cancer. These variants could serve as early biomarkers for identifying RAI-R status, enabling more tailored treatment strategies.