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

Kohei Hagiwara, Sivaraman Natarajan, Zhaoming Wang, Haseeb Zubair, Heather L Mulder, Li Dong, Emily M Plyler, Padma Thimmaiah, Xiaotu Ma, Kristen K Ness, Zhenghong Li, Daniel A Mulrooney, Carmen L Wilson, Yutaka Yasui, Melissa M Hudson, John Easton, Leslie L Robison, Jinghui Zhang
Cancer Discovery Apr 2023

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 survivors of Hodgkin lymphoma, 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, whereas therapy-related CH remains stable decades after 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.




Institution Type


Indication / Modality


Goal of Study

CHIP, Clinical Profiling

PAD Project


Analytes Assessed

SNV, InDels



Proof Point Demonstrated

Clonality, Phylogeny, Co-occurrence, Sensitivity