# Association of high‐dose radioactive iodine therapy with PPM1D‐mutated clonal hematopoiesis in older individuals

## TL;DR

High-dose radioactive iodine therapy in older thyroid cancer patients is linked to increased clonal hematopoiesis, especially with PPM1D mutations.

## Contribution

Identifies a novel association between high-dose RAIT and PPM1D-mutated clonal hematopoiesis in older individuals.

## Key findings

- High-dose RAIT increased CH prevalence with VAF >2% in patients aged ≥50 (OR = 2.44).
- PPM1D mutations occurred more frequently in high-dose RAIT recipients (13%) compared to controls (2%).
- Truncating PPM1D mutations confer a selective advantage under high-dose RAIT and with older age.

## Abstract

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.

In thyroid cancer patients, high‐dose (≥7.4 GBq) radioactive iodine therapy (RAIT) was associated with a higher prevalence of clonal hematopoiesis (variant allele frequency >2%) in individuals aged ≥50 years (OR = 2.44). In silico analyses showed that truncating PPM1D mutations conferred a selective advantage under these conditions. These findings underscore the need to optimize RAIT dosing.