Evolutionary dynamics in the decades preceding acute myeloid leukaemia

Somatic evolution in ageing tissues underlies many cancers. However, our quantitive understanding of the rules governing this pre-cancerous evolution remains incomplete. Here we exploit a unique collection of serial blood samples collected annually up to 15 years prior to diagnosis of acute myeloid leukaemia (AML) 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 AML 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 which 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 AML. Once established in the blood, the dynamics of driver mutations are highly predictable. Trajectories are shaped by strong clonal competition between lineages with limited evidence of other extrinsic factors playing a major role. Our data show that the clonal dynamics of blood are consistent with a set of remarkably simple evolutionary rules which strike a balance between chance and determinism.