Abstract 499: Accelerated clonal hematopoiesis in survivors of childhood cancer: A report for the St. Jude Lifetime Cohort Study
Authors: Hagiwara Kohei , Wang Zhaoming , Zubair Haseeb , Easton John , Mulder Heather L. , Ma Xiaotu , Ness Kristen K. , Li Zhenghong , Mulrooney Daniel A. , Wilson Carmen L. , Yasui Yutaka , Hudson Melissa M. , Robison Leslie L. , Zhang Jinghui 
Published: June 2022

Abstract
Survivors of childhood cancer are at risk for a spectrum of adverse outcomes including hematological malignancies and cardiovascular diseases, which in other populations have been associated with clonal hematopoiesis (CH), an age-related clonal expansion of hematopoietic stem cells. Here we present the first comprehensive CH analysis including 2,872 pediatric cancer survivors from the St. Jude Lifetime Cohort (median follow-up of 26 years from cancer diagnosis; median age of 31 years at blood draw) using deep sequencing (10,000 ×) over 39 CH genes on DNA derived from peripheral blood. As a comparison group, 324 age-, sex- and race/ethnicity-frequency-matched community controls (median age of 35 years at blood draw) were also analyzed. To detect rare CH variants, a machine-learning approach was applied, which characterized true variants as outliers in a genomic context-specific error profile. Digital droplet PCR validation was performed for 543 variants (323 positive [allele frequency: median 0.003, range 0.001 to 0.255] and 220 negative) out of 1,450 putative variants. The 907 untested variants were inferred using the 543 experimentally validated variants’ status as a training set. Analyses considered mutation status by the 555 positive variants and clinical data including age, sex, and detailed cancer treatment exposures. CH was detected in 15% (95% Confidence Interval (CI): 13.7 to 16.3) of survivors and 8.6% (95% CI: 5.6 to 11.7) of controls in an age-dependent manner: 10.6% (survivors) vs. 6.3% (controls) for ages in year 18 - 29; 13.5% vs. 5.8% for 30 - 39; 26.3% vs. 13.2% for 40 - 49; 28.1% vs. 17.2% for &gt; 50. We also observed that the alterations in DNMT3A, TP53, STAT3, KRAS and TET2 became more prevalent as the survivors aged: combined proportion for the 5 genes, 61% for ages in year &lt; 30; 72% for 30 - 40; 77% for 40 - 50; 87% for &gt; 50. Analysis of longitudinal samples available for 73 survivors with 180 time points (median interval 4.6 years [range: 2.07 to 8.0 years]) confirmed that clones with these gene mutations had a higher growth rate than those without (p=0.034), suggesting fitness advantages in hematopoietic stem cell context. Multivariable analysis adjusted for treatment indicated that CH development is associated with cumulative dose of alkylating agents (Odds Ratio (OR) for 1st tertile 1.77 [95% CI: 1.22 to 2.57], 2nd tertile 2.72 [95% CI: 1.83 to 4.04], and 3rd tertile 2.92 [95% CI: 2.03 to 4.02], relative to the unexposed) and estimated radiotherapy-dose to active bone marrow (OR for 1st tertile 0.98 [95% CI: 0.68 to 1.40], 2nd tertile 1.06 [0.77 to 1.47], and 3rd tertile 1.57 [1.15 to 2.14], relative to the unexposed), supporting the hypothesis that CH development in survivors is primarily driven by prior therapy. This study identified accelerated CH development in pediatric cancer survivors, which may represent an important genomic biomarker predictive of future adverse health risks.
Citation Format: Kohei Hagiwara, Zhaoming Wang, Haseeb Zubair, John Easton, Heather L. Mulder, Xiaotu Ma, Kristen K. Ness, Zhenghong Li, Daniel A. Mulrooney, Carmen L. Wilson, Yutaka Yasui, Melissa M. Hudson, Leslie L. Robison, Jinghui Zhang. Accelerated clonal hematopoiesis in survivors of childhood cancer: A report for the St. Jude Lifetime Cohort Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 499.