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Longitudinal dynamics of clonal haematopoiesis identifies gene-specific fitness effects


ABSTRACT: The prevalence of clonal haematopoiesis of indeterminate potential (CHIP) in healthy individuals increases rapidly from age 60 onwards and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in stem cells that are also drivers of myeloid malignancies. Since mutations in stem cells often drive leukaemia, we hypothesised that stem cell fitness substantially contributes to transformation from CHIP to leukaemia. Stem cell fitness is defined as the proliferative advantage over cells carrying no or only neutral mutations. It is currently unknown whether mutations in different CHIP genes lead to distinct fitness advantages that could form the basis for patient stratification. We set out to quantify the fitness effects of CHIP drivers over a 12-year timespan in older age, using longitudinal error-corrected sequencing data. Two key results support the possibility for individualised clinical monitoring of CHIP: (i) We developed a new filtering method to extract fitness effects from longitudinal data using Bayesian inference, while taking into account individual mutational context and co-occurrence of mutations, and thus quantify the growth potential of variants within each individual. (ii) We show that gene-specific fitness differences can outweigh inter-individual variation and therefore could form the basis for personalised clinical management in the future.

ORGANISM(S): Homo sapiens

PROVIDER: GSE178936 | GEO | 2022/05/03

REPOSITORIES: GEO

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