Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are two types of clonal hematopoiesis (CH) associated with hematological parameters and malignancy risk. Here we show, in genomic data from 546,090 biobank participants, that co-occurring CH (≥2 CH mutations detected) is present in 1.6% of cancer-free individuals and shows strong evidence for selection (up to 804x enrichment). Co-occurrence is more frequent in those with a prior cancer (3.6%), suggesting treatment-induced selection. Acquisition of CHIP usually precedes mCAs with co-occurrences manifesting stronger phenotypic disruptions in telomere attrition and hematologic parameters than component CH events. Individuals with co-occurring CH have pronounced elevations in risk of myeloid and lymphoid malignancies (HRs>40), particularly when CHIP and mCAs overlap genomically. Our findings indicate CH co-occurrences are selected for in the aging population and identify CH clones with notable implications for future malignancy risk.
Acknowledgements
This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH). The contributions of the NIH authors were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. This work was also supported in part by the National Institutes of Health (Grants: R01HL146500 and R01HL165061). Acknowledgements for all contributing TOPMed studies are provided as supplementary information.
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The authors declare the following competing interests: S.R. has consulted for Amgen, Inc. E.K.S. received institutional grant support from Bayer and Northpond Laboratories over the past 3 years. Y.C. provided consultancy services to Need and Bayer for work outside the scope of the manuscript. M.H.C. has received grant support from Bayer and Genentech, and consulting fees from Apogee Therapeutics and BMS, unrelated to the current work. L.M.R. is a consultant for the TOPMed Administrative Coordinating Center (through Westat). S.S.R. is a consultant for Westat, the Administrative Coordinating Center for the NHLBI TOPMed program. The remaining authors declare no competing interests.
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Barnao, K.M., Hubbard, A.K., Chan, I.C.C. et al. Co-occurring clonal hematopoiesis exhibits strong selection and high leukemia risk. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73302-x
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DOI: https://doi.org/10.1038/s41467-026-73302-x
