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

Clonal hematopoiesis (CH) refers to the presence of hematopoietic stem cell subpopulations that have become genetically distinct from the germline genome via acquisition of somatic mutations. While CH is an age-related phenomenon in the general population, it can also be induced by exogenous factors such as chemotherapy and radiotherapy. A study in the St. Jude Lifetime Cohort (2,860 long-term survivors of pediatric cancer with a median follow-up of 23.5 years; compared with 324 community controls) using deep-sequencing over 39 CH-related genes found mutations in 15% of the survivors, significantly higher than the 8.5% in the controls. CH in survivors was associated with exposures to alkylating agents, radiation, and bleomycin. Therapy-related CH showed significant enrichment in STAT3, characterized as a CH-gene specific to Hodgkin lymphoma survivors, and TP53. Serial-sample tracking revealed that larger clone size was a predictor for future expansion of age-related CH clones, while therapy-related CH remained stable decades post-treatment. The authors conclude that these data depict the distinct dynamics of age- versus therapy related CH subtypes, and support the need for longitudinal monitoring to determine the potential contributions to late effects.