Evolutionary dynamics in the years preceding acute myeloid leukaemia

Abstract Somatic evolution in ageing tissues underlies many cancers 1,2 . However, our quantitative understanding of the rules governing this pre-cancerous evolution remains incomplete. Here we exploit a unique collection of serial blood samples 3 , collected annually for up to a decade and beginning as early as 15 years before diagnosis of acute myeloid leukaemia, to provide a quantitative description of pre-cancerous evolutionary dynamics. Using deep duplex sequencing and evolutionary theory, we quantify the acquisition ages and fitness effects of the key driver events in acute myeloid leukaemia development. The first driver mutations are typically acquired in the first few decades of life, when the blood remains highly polyclonal. These early slow-growing clones subsequently acquire multiple further driver mutations that confer selective advantages up to 100-fold larger than the early drivers. These faster-growing clones harbouring multiple driver mutations can cause complete somatic sweeps of the blood decades before diagnosis, a feature strongly associated with future acute myeloid leukaemia. Our data show that the clonal dynamics of blood are consistent with a set of remarkably simple evolutionary rules that strike a balance between chance and determinism.