Clonal hematopoiesis in survivors of childhood cancer

Clonal hematopoiesis (CH), defined as the clonal expansion of mutated hematopoietic stem and progenitor cells, is associated with the development of hematologic cancers, cardiovascular disease (CVD), and other adverse health outcomes.(1-3) CH is thought to expand with older age resulting in an increasing variant allele frequency (VAF) over time.(1) Thus, the frequency of CH detection in a given population is dependent on the age and sensitivity of sequencing techniques, with ultradeep sequencing detecting low-VAF variants.(4) CH is also associated with race, smoking, and exposure to oncologic therapy.(5-8) Environmental stressors may increase the likelihood of both mutational acquisition and clonal fitness. Oncologic therapy has been previously shown to increase the fitness advantage of mutant hematopoietic stem and progenitor cells, particularly those bearing mutations in the DNA damage response (DDR) pathway, including TP53, PPM1D, and CHEK2.(9,10) However, the extent to which therapy-induced CH expansion persists after the completion of therapy has not been defined. Survivors of childhood cancer are a growing cohort in whom CH has not been routinely assessed; an estimated 500 000 survivors are currently alive in the United States.(11) Despite excellent 5-year survival rates, survivors of childhood cancer remain at a lifelong risk of premature morbidity and mortality, including a 15-fold risk of death due to subsequent malignant neoplasm (SMN) and a sevenfold risk of death due to CVD,(12,13) with particularly pronounced risks noted after exposure to chemotherapy and/or radiotherapy, generally in a dose-dependent fashion.(14,15) Survivors have also been noted to have higher rates of premature aging.(16,17) We hypothesized that CH mutations would be enriched in survivors of childhood cancer previously exposed to cytotoxic therapy because of the increased selection of preexisting CH clones, which may, in part, explain their increased risk of SMN, CVD, and premature aging. Here, we compared the frequency of CH between survivors of childhood cancer and matched controls using error-corrected deep sequencing. We show that survivors have higher frequencies of CH than age-matched controls and that this increased frequency of CH persists for many years after treatment. This was a retrospective case-control study survivors of childhood, adolescent, and young adult cancer and matched controls. Cases included individuals diagnosed with a solid tumor or lymphoma at <= 28 years of age and treated with systemic chemotherapy and/or radiotherapy who were >= 13 years of age and >= 6 months since the completion of therapy at peripheral blood sample collection during routine clinical visits. Age-matched controls (5-year age groups) with and without a history of cancer were included, given the evidence of shared genomic risk factors between cancer and CH. Controls included 1 group of treatment-naive individuals recently diagnosed with a nonhematologic cancer at Sloan Kettering Cancer Center and another group of healthy adolescents and young adults from Washington University without a cancer history.