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

Clonal hematopoiesis (CH) occurs frequently in older individuals and predisposes them to development of hematological malignancies. To characterize evolution of CH, we performed error-corrected smMIP-based sequencing on 7074 sequential samples from 3359 individuals in the prospective population-based Lifelines cohort. The cohort was linked to the Netherlands Cancer Registry for incident diagnoses of hematological cancer. Spliceosome mutations (SF3B1, SRSF2, U2AF1) and JAK2 mutated clones showed the highest growth rates over a median 3.6-year period, while clone size for DNMT3A and TP53 increased marginally. Traditional cancer risk factors did not affect clonal growth rate. Risk of developing myeloid malignancy was highest for participants with JAK2, spliceosome, N/KRAS or TP53 mutations and was absent for DNMT3A. We observed patterns of early and late mutation acquisition in the evolution of clonal hematopoiesis. Nearly all participants developing myeloid malignancy suffered from peripheral cytosis or cytopenia, and variable clonal expansion or mutation acquisition preceded this development. These results provide important insight into high-risk evolutionary patterns for monitoring of CH.