The longitudinal dynamics and natural history of clonal haematopoiesis

Margarete A. Fabre, José Guilherme Almeida, Edoardo Fiorillo, Emily Mitchell, Aristi Damaskou, Justyna Rak, Valeria Orrù, Michele Marongiu, Michael Spencer Chapman, M. S. Vijayabaskar, Joanna Baxter, Claire Hardy, Federico Abascal, Nicholas Williams, Jyoti Nangalia, Iñigo Martincorena, Peter J. Campbell, Eoin F. McKinney, Francesco Cucca, Moritz Gerstung () and George S. Vassiliou ()
Additional contact information
Margarete A. Fabre: Wellcome Sanger Institute, Wellcome Genome Campus
José Guilherme Almeida: European Bioinformatics Institute EMBL-EBI, Wellcome Genome Campus
Edoardo Fiorillo: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche
Emily Mitchell: Wellcome Sanger Institute, Wellcome Genome Campus
Aristi Damaskou: University of Cambridge
Justyna Rak: University of Cambridge
Valeria Orrù: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche
Michele Marongiu: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche
Michael Spencer Chapman: Wellcome Sanger Institute, Wellcome Genome Campus
M. S. Vijayabaskar: University of Cambridge
Joanna Baxter: University of Cambridge
Claire Hardy: Wellcome Sanger Institute, Wellcome Genome Campus
Federico Abascal: Wellcome Sanger Institute, Wellcome Genome Campus
Nicholas Williams: Wellcome Sanger Institute, Wellcome Genome Campus
Jyoti Nangalia: Wellcome Sanger Institute, Wellcome Genome Campus
Iñigo Martincorena: Wellcome Sanger Institute, Wellcome Genome Campus
Peter J. Campbell: Wellcome Sanger Institute, Wellcome Genome Campus
Eoin F. McKinney: University of Cambridge
Francesco Cucca: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche
Moritz Gerstung: European Bioinformatics Institute EMBL-EBI, Wellcome Genome Campus
George S. Vassiliou: Wellcome Sanger Institute, Wellcome Genome Campus

Nature, 2022, vol. 606, issue 7913, 335-342

Abstract: 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 haematopoiesis1–4. 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 limited5,6. 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 (SRSF2P95H). 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.

Date: 2022
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DOI: 10.1038/s41586-022-04785-z

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