Shared and distinct genetic etiologies for different types of clonal hematopoiesis

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, John R. B. Perry (), Vijay G. Sankaran () and Mitchell J. Machiela ()
Additional contact information
Derek W. Brown: National Cancer Institute
Liam D. Cato: Dana-Farber Cancer Institute, Harvard Medical School
Yajie Zhao: University of Cambridge School of Clinical Medicine
Satish K. Nandakumar: Dana-Farber Cancer Institute, Harvard Medical School
Erik L. Bao: Dana-Farber Cancer Institute, Harvard Medical School
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
Vijay G. Sankaran: Dana-Farber Cancer Institute, Harvard Medical School
Mitchell J. Machiela: National Cancer Institute

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41315-5

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