Dynamics of age- versus therapy-related clonal hematopoiesis in long-term survivors of pediatric cancer.

We present the first comprehensive investigation of clonal hematopoiesis (CH) in 2,860 long-term survivors of pediatric cancer with a median follow-up time of 23.5 years. Deep-sequencing over 39 CH-related genes reveals mutations in 15% of the survivors, significantly higher than the 8.5% in 324 community controls. CH in survivors is associated with exposures to alkylating agents, radiation, and bleomycin. Therapy-related CH shows significant enrichment in STAT3, characterized as a CH-gene specific to Hodgkin lymphoma survivors, and TP53. Single-cell profiling of peripheral blood samples revealed STAT3 mutations predominantly present in T-cells and contributed by SBS25, a mutational signature associated with procarbazine exposure. Serial-sample tracking reveals that larger clone size is a predictor for future expansion of age-related CH clones, while therapy-related CH remains stable decades post-treatment. These data depict the distinct dynamics of these CH subtypes and support the need for longitudinal monitoring to determine the potential contribution to late effects.