Evolutionary landscape of clonal hematopoiesis in 3,359 individuals from the general population

Knowledge about evolution of clonal hematopoiesis, which may drive malignant progression, is crucial for clinical decision-making. We investigated the landscape of clonal evolution by error-corrected sequencing on 7,045 sequential samples from 3,359 individuals in the prospective population-based Lifelines cohort, with a special focus on cytosis and cytopenia. Spliceosome (SRSF2/U2AF1/SF3B1) and JAK2 mutated clones show highest growth rates over a median 3.6-year period, while clone sizes for DNMT3A and TP53 increase only marginally, independent of cytosis or cytopenia. Nevertheless, large differences are observed between individuals carrying the same mutation, indicative of modulation by non-mutation-related factors. Clonal expansion is not dependent on classical cancer risk factors (e.g., smoking). Risk for incident myeloid malignancy diagnosis is highest for JAK2, spliceosome, or TP53 mutations and absent for DNMT3A, and it is mostly preceded by cytosis or cytopenia. The results provide important insight into high-risk evolutionary patterns to guide monitoring of "CHIP" and "CCUS."