Association of high-dose radioactive iodine therapy with PPM1D-mutated clonal hematopoiesis in older individuals.

While radioactive iodine therapy (RAIT) has been an effective treatment for thyroid cancer, its link to clonal hematopoiesis (CH) has been yet underexplored. In this study, error-corrected sequencing (median depth: 1926×) of 93 CH-related genes was performed from the blood samples of 358 thyroid cancer patients, including 110 controls (no RAIT) and 248 RAIT recipients. RAIT recipients were stratified into low- and high-dose groups using a 7.4 GBq cutoff. Multivariable logistic regression revealed that the high-dose group had a higher CH prevalence with variant allele frequency (VAF) higher than 2% compared to controls, especially in patients aged ≥50 (OR = 2.44, CI = 1.04-6.00, P = 0.04). Thirteen genes had mutations with VAF >2%, with DNMT3A, TET2, and PPM1D being the most common. Notably, only the PPM1D mutations were significantly linked to RAIT, occurring more frequently in the high-dose group (13%) compared to the low-dose group (5%) or controls (2%) at a VAF cutoff of 0.5%. In silico analyses indicated that truncating PPM1D mutations confer a selective advantage under high-dose RAIT and with older age. Although the prognostic implications of PPM1D-mutated CH remain to be further elucidated, these findings offer valuable insights for optimizing RAIT dosing in thyroid cancer patients.