The longitudinal dynamics and natural history of clonal haematopoiesis.
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Authors
Fabre, Margarete A
de Almeida, José Guilherme
Fiorillo, Edoardo
Mitchell, Emily
Damaskou, Aristi
Rak, Justyna
Vijayabaskar, M S
Baxter, Joanna
Hardy, Claire
McKinney, Eoin F
Cucca, Francesco
Publication Date
2022-06-01Journal Title
Nature
ISSN
0028-0836
Volume
606
Issue
7913
Pages
335-342
Language
eng
Type
Article
This Version
VoR
Metadata
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Fabre, M. A., de Almeida, J. G., Fiorillo, E., Mitchell, E., Damaskou, A., Rak, J., Orrù, V., et al. (2022). The longitudinal dynamics and natural history of clonal haematopoiesis.. Nature, 606 (7913), 335-342. https://doi.org/10.1038/s41586-022-04785-z
Description
Funder: European Research Council
Abstract
Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis<sup>1-4</sup>. The understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited<sup>5,6</sup>. Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A and TP53) to more than 50% per year (SRSF2<sup>P95H</sup>). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2-mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.
Keywords
Clone Cells, Humans, Longitudinal Studies, Phylogeny, Aging, Mutation, Genome, Human, Aged, Middle Aged, Clonal Hematopoiesis
Sponsorship
Wellcome Trust (098051, WT098051, 104064/Z/14/Z)
Identifiers
PMC9177423, 35650444
External DOI: https://doi.org/10.1038/s41586-022-04785-z
This record's URL: https://www.repository.cam.ac.uk/handle/1810/338718
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