Somatic mutations in healthy and leukemic blood progenitors reveal evolutionary mechanisms underlying childhood leukemia and differential patient outcome

The acquisition of oncogenic mutations with age is believed to be rate limiting for carcinogenesis. However, the incidence of leukemia in children is higher than in young adults yet their cells are less damaged by age. Here, we compared by whole genome sequencing individual hematopoietic stem and progenitor cells (HSPCs) and pediatric acute myeloid leukemia (pAML) 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, which 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 survival. Our study provides new insights into the etiology of pAML and underscores the clinical potential of whole genome sequencing in pediatric leukemia.EGA study EGAS00001004593