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The longitudinal dynamics and natural history of clonal haematopoiesis

Author

Listed:
  • Margarete A. Fabre

    (Wellcome Sanger Institute, Wellcome Genome Campus
    University of Cambridge
    University of Cambridge)

  • 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
    University of Cambridge
    University of Cambridge)

  • Aristi Damaskou

    (University of Cambridge
    University of Cambridge)

  • Justyna Rak

    (University of Cambridge
    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
    University of Cambridge
    University of Cambridge)

  • M. S. Vijayabaskar

    (University of Cambridge
    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
    University of Cambridge)

  • Jyoti Nangalia

    (Wellcome Sanger Institute, Wellcome Genome Campus
    University of Cambridge
    University of Cambridge)

  • Iñigo Martincorena

    (Wellcome Sanger Institute, Wellcome Genome Campus)

  • Peter J. Campbell

    (Wellcome Sanger Institute, Wellcome Genome Campus
    University of Cambridge)

  • Eoin F. McKinney

    (University of Cambridge)

  • Francesco Cucca

    (Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche
    Università degli Studi di Sassari)

  • Moritz Gerstung

    (European Bioinformatics Institute EMBL-EBI, Wellcome Genome Campus
    German Cancer Research Centre DKFZ)

  • George S. Vassiliou

    (Wellcome Sanger Institute, Wellcome Genome Campus
    University of Cambridge
    University of Cambridge)

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.

Suggested Citation

  • Margarete A. Fabre & José Guilherme Almeida & Edoardo Fiorillo & Emily Mitchell & Aristi Damaskou & Justyna Rak & Valeria Orrù & Michele Marongiu & Michael Spencer Chapman & M. S. Vijayabaskar & Joann, 2022. "The longitudinal dynamics and natural history of clonal haematopoiesis," Nature, Nature, vol. 606(7913), pages 335-342, June.
  • Handle: RePEc:nat:nature:v:606:y:2022:i:7913:d:10.1038_s41586-022-04785-z
    DOI: 10.1038/s41586-022-04785-z
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    Cited by:

    1. Mariana Shumliakivska & Guillermo Luxán & Inga Hemmerling & Marina Scheller & Xue Li & Carsten Müller-Tidow & Bianca Schuhmacher & Zhengwu Sun & Andreas Dendorfer & Alisa Debes & Simone-Franziska Glas, 2024. "DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Heather E. Machado & Nina F. Øbro & Nicholas Williams & Shengjiang Tan & Ahmed Z. Boukerrou & Megan Davies & Miriam Belmonte & Emily Mitchell & E. Joanna Baxter & Nicole Mende & Anna Clay & Philip Anc, 2023. "Convergent somatic evolution commences in utero in a germline ribosomopathy," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Md Mesbah Uddin & Seyedmohammad Saadatagah & Abhishek Niroula & Bing Yu & Whitney E. Hornsby & Shriienidhie Ganesh & Kim Lannery & Art Schuermans & Michael C. Honigberg & Alexander G. Bick & Peter Lib, 2024. "Long-term longitudinal analysis of 4,187 participants reveals insights into determinants of clonal hematopoiesis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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