TP53/p53 alterations in thyroid cancer: dedifferentiation, radioiodine refractoriness and risk stratification

Most thyroid cancers are differentiated tumours with favourable outcomes, but a clinically important minority develops invasion, distant metastasis, loss of radioiodine uptake and histological dedifferentiation. TP53 encodes p53, a tumour suppressor that coordinates DNA-damage responses, cell-cycle arrest, apoptosis and genome stability. In thyroid cancer, TP53/p53 abnormalities show a stage-dependent pattern. They are uncommon in conventional low-risk differentiated thyroid cancer (DTC), but become enriched in high-grade DTC, poorly differentiated thyroid carcinoma, anaplastic thyroid carcinoma, radioiodine-refractory disease and rapidly progressive tumours. This Review integrates the 2022 WHO classification, the 2025 American Thyroid Association guideline, early pathology studies, modern genomic cohorts, mechanistic models and recent therapeutic evidence. Current data support TP53/p53 alteration as both a marker and a functional contributor to high-grade transformation and clonal progression. In radioiodine refractoriness, TP53 abnormality is best interpreted as part of a multistep progression background involving dedifferentiation and clonal selection, rather than as a single cause of iodine-uptake loss. Clinically, TP53 testing is most useful in high-risk, progressive or treatment-refractory disease and should be interpreted together with histology, radioiodine avidity, TERT, BRAF/RAS, PI3K/AKT alterations and treatment response.