Clonal hematopoiesis in survivors of childhood cancer.
Authors: Friedman Danielle Novetsky , Chan Irenaeus Chi-Chung , Moskowitz Chaya S. , Li Shanita , Turner Kimberly , Liu Jie , Bouvier Nancy , Walsh Michael Francis , Spitzer Barbara , Kung Andrew , Berger Michael F. , Cooper Megan A. , Pusic Iskra , Uy Geoffrey L. , Link Daniel C , Druley Todd E , Diaz Luis A. , Levine Ross L. , Shukla Neerav , BOLTON KELLY L 
Published: June 2023

10014

Background: Subsequent malignancies and cardiovascular (CV) disease are the leading cause of premature death in childhood cancer survivors, a population also at risk for premature aging. Clonal hematopoiesis (CH), the age-related clonal expansion of mutated hematopoietic stem cells, is a prominent risk factor for early-onset malignant and CV disease. Data are lacking on the prevalence of CH in childhood cancer survivors. Methods: We evaluated the prevalence of CH in a retrospective case-control study of childhood cancer survivors and matched controls (all ≥13 years of age). Cases included individuals diagnosed with a solid tumor or lymphoma at age ≤25 years who were ≥6-months from completion of chemotherapy and/or radiotherapy. Age-matched controls (5-year age bins) with and without a history of cancer were included, given evidence of shared genomic risk factors between cancer and CH. Samples were batched and sequenced at an average depth of 19,830x using a custom, targeted amplicon-based UMI sequencing platform (ArcherDX), which included full exons of DMNT3A, TET2, ASXL1, TP53, CHEK2 and targeted regions of PPM1D, SRSF2, SF3B1, JAK2. Mutations at a variant allelic frequency (VAF) ≥ 0.02% were identified with VAF > 2% considered clinically significant. Logistic regression adjusted for age, gender, and race was used to test for an association between CH and case-control status. Results: Samples were analyzed from 104 childhood cancer survivors (median age 19 years [y], range, 13-49y; median time since end-of-therapy: 10y, range 0.5-39y), 71 controls with untreated, newly diagnosed cancer (median age 25y, range 8-48y), and 68 healthy controls (median age 23y, range, 15-51y). The frequency of CH was higher in childhood cancer survivors compared to controls across ages with CH detected in 36.5% of survivors and 20.1% of controls (OR 3.2, 95% CI, 1.6-6.1). The enrichment of CH in survivors was observed both relative to healthy controls (OR 2.3, 95% CI 1.1-5.3) and treatment-naïve solid tumor controls (OR 5.0, 95% CI, 2.1-13.7). A trend toward a stronger association for CH mutations with VAF > 2% (OR 10.9, 95% CI, 1.9-60.7) compared to VAF < 2% (OR 2.7, 95% CI, 1.4-5.2) was observed. The most commonly mutated genes were in the DTA ( DNMT3A, TET2 and ASXL1) and DDR ( PPM1D, TP53 and CHEK2) classes. While a higher proportion of both DTA and DDR mutations was noted among survivors compared to controls, the enrichment of DDR mutations was stronger than DTA (OR 7.1, 95% CI 2.8-18.3 for DDR; OR 2.3, 95% CI 1.1-4.6 for DTA). A sub-analysis of 5 year survivors showed a higher frequency of CH in this cohort compared to controls (OR 2.8, 95% CI, 1.3-5.9). Conclusions: Childhood cancer survivors have higher frequencies of CH than age-matched controls, which persists for years after treatment. These data suggest that CH may, in part, drive the long-term premature multimorbidity seen in survivors. Longitudinal assessment of CH among survivors may be indicated to elucidate these associations.