Abstract 3051: On the origin of pediatric leukemia: studying somatic mutations in human blood

Abstract

The acquisition of oncogenic mutations with age is believed to be rate limiting for carcinogenesis and aging is the biggest risk factor for cancer. However, children can also develop cancers even though their cells are less damaged by age. Here, we studied the cellular origin and time of onset during development of pediatric acute myeloid leukemia (pAML) to increase our understanding of why children can get cancer. We compared by whole genome sequencing individual hematopoietic stem and progenitor cells (HSPCs) and pAML blasts of the same leukemic bone marrow as well as nonmatching healthy HSPCs. We found that the number of clonal mutations in the majority of pAML cases was increased and mutational process contribution altered as compared to normal HSPCs, showing activity of specific processes that are either unique to fetal development or normally not observed in healthy HSPCs. These observations could be explained by altered selection dynamics early in life. Surprisingly, pAML cases with an overall mutation burden comparable to age matched healthy HSPCs showed worse overall and event-free survival. Identifying shared somatic mutations between individual HSPC clones and pAML using single-cell genotyping allowed us to pinpoint the developmental lineage that gave rise to the pAML. Our study provides new insights into the etiology of pAML and underscores the clinical potential of whole genome sequencing in pediatric leukemia. Citation Format: Arianne Brandsma. On the origin of pediatric leukemia: studying somatic mutations in human blood [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3051.