Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects

Clonal haematopoiesis of indeterminate potential (CHIP) increases rapidly in prevalence beyond age 60 and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in hematopoietic stem and progenitor cells (HSPCs). Since mutations in HSPCs often drive leukaemia, we hypothesised that HSPC fitness substantially contributes to transformation from CHIP to leukaemia. HSPC fitness is defined as the proliferative advantage over cells carrying no or only neutral mutations. If mutations in different genes lead to distinct fitness advantages, this could enable patient stratification. We quantified the fitness effects of mutations over 12 years in older age using longitudinal sequencing and developed a filtering method that considers individual mutational context alongside mutation co-occurrence to quantify the growth potential of variants within individuals. We find that gene-specific fitness differences can outweigh inter-individual variation and therefore could form the basis for personalised clinical management.