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February 7, 2023 @ 1:00 pm - 2:00 pm
Chair, Department of Computational Biology
St Jude Children’s Research Hospital
Therapy-related clonal evolution in pediatric cancer patients and long-term survivors
Understanding the short-term and long-term therapy-related effect on the genomes of pediatric cancer and survivors is essential for reducing the mortality associated with cancer relapse and the accelerated physiological aging of long-term survivors. We present the discovery of therapy-related mutagenesis processes, including those involved in structural variations (SVs) in relapsed pediatric acute lymphoblastic leukemias and metastatic osteosarcoma, which give rise to resistant clones under the selective pressure of exposure to cytotoxic agents. We also present the dynamics of age- versus therapy-related clonal hematopoiesis (CH) in long-term survivors of pediatric cancer with a median follow-up time of 23.5 years. 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.