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Shared and distinct genetic etiologies for different types of clonal hematopoiesis

Author

Listed:
  • Derek W. Brown

    (National Cancer Institute
    National Cancer Institute)

  • Liam D. Cato

    (Dana-Farber Cancer Institute, Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Yajie Zhao

    (University of Cambridge School of Clinical Medicine)

  • Satish K. Nandakumar

    (Dana-Farber Cancer Institute, Harvard Medical School
    Broad Institute of MIT and Harvard
    Albert Einstein Cancer Center, Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine)

  • Erik L. Bao

    (Dana-Farber Cancer Institute, Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Eugene J. Gardner

    (University of Cambridge School of Clinical Medicine)

  • Aubrey K. Hubbard

    (National Cancer Institute)

  • Alexander DePaulis

    (National Cancer Institute)

  • Thomas Rehling

    (National Cancer Institute)

  • Lei Song

    (National Cancer Institute)

  • Kai Yu

    (National Cancer Institute)

  • Stephen J. Chanock

    (National Cancer Institute)

  • John R. B. Perry

    (University of Cambridge School of Clinical Medicine
    University of Cambridge School of Clinical Medicine)

  • Vijay G. Sankaran

    (Dana-Farber Cancer Institute, Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Mitchell J. Machiela

    (National Cancer Institute)

Abstract

Clonal hematopoiesis (CH)—age-related expansion of mutated hematopoietic clones—can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk.

Suggested Citation

  • Derek W. Brown & Liam D. Cato & Yajie Zhao & Satish K. Nandakumar & Erik L. Bao & Eugene J. Gardner & Aubrey K. Hubbard & Alexander DePaulis & Thomas Rehling & Lei Song & Kai Yu & Stephen J. Chanock &, 2023. "Shared and distinct genetic etiologies for different types of clonal hematopoiesis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41315-5
    DOI: 10.1038/s41467-023-41315-5
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    References listed on IDEAS

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