Co-occurring clonal hematopoiesis exhibits strong selection and high leukemia risk

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.

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Publication Details

Journal
Nature Communications
Published
2026-05-21
DOI
https://doi.org/10.1038/s41467-026-73302-x
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
0.00
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article

Co-occurring clonal hematopoiesis exhibits strong selection and high leukemia risk

Aubrey K. Hubbard, Joshua P. Lewis, Michael H. Cho, Corey D. Young et al.
Nature Communications
Acute Myeloid Leukemia Research
article

Co-occurring clonal hematopoiesis exhibits strong selection and high leukemia risk

Aubrey K. Hubbard, Joshua P. Lewis, Michael H. Cho, Corey D. Young, Laura M. Raffield, Wendy S.W. Wong, Joshua C. Bis, Rebecca L. Kelly, Marguerite R. Irvin, Yasminka A. Jakubek, Neal D. Freedman, Kara M. Barnao, Duc Tran, Jennifer A. Smith, Andrew D. Johnson, P Desai, Donna Arnett, Albert V. Smith, April P. Carson, Paul Scheet, Adrienne Stilp, R Mathias, P L Auer, A Bick, S S Redline, S Rich, Mitchell J. Machiela, Eric Boerwinkle, Edwin K. Silverman, Daniel Levy, Giulio Genovese, Sharon L. R. Kardia, Kari E. North, Braxton D. Mitchell, Nathan Pankratz, Bruce M. Psaty, Alexander P. Reiner, Kelly L. Bolton, Belynda Hicks, Kristine Jones, Daniel I. Chasman, Michael H. Preuss, Charles Kooperberg, Stephen J. Chanock, Jerome I. Rotter, Myriam Fornage, Weiyin Zhou, Xiuqing Guo, Wen-Yi Huang, Margaret F. Doyle, Yun Li, Kathleen C. Barnes, Patricia A. Peyser, Amy Hutchinson, Derek W. Brown, Taralynn M. Mack, Yin Cao, Nancy Heard-Costa, Irenaeus C. C. Chan, Jennifer A. Brody, Ruth J. F. Loos
article en

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.

Nature Communications
Broad Institute (US), Boston University (US), University of Vermont (US), University of North Carolina at Chapel Hill (US), Leidos (United States) (US), University of Copenhagen (DK), University of Maryland, Baltimore (US), Brigham and Women's Hospital (US), National Institutes of Health (US), University of Minnesota (US), The University of Texas MD Anderson Cancer Center (US), Harvard University (US), University of Kentucky (US), University of South Carolina (US), University of Washington (US), Medical College of Wisconsin (US), Washington University in St. Louis (US), Cornell University (US), University of Michigan (US), Novo Nordisk Foundation (DK), UCLA Medical Center (US), Jackson Memorial Hospital (US), University of Mississippi Medical Center (US), University of Alabama at Birmingham (US), Fred Hutch Cancer Center (US), National Heart, Lung, and Blood Institute (US), Frederick National Laboratory for Cancer Research (US), National Cancer Institute (MY), National Institute of Allergy and Infectious Diseases (US), National Cancer Institute (US), Statistical Research (United States) (US), Harbor–UCLA Medical Center (US), Alvin J. Siteman Cancer Center (US), Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc. (United States), University of Virginia (US), Vanderbilt University Medical Center (US), The University of Texas Health Science Center at Houston (US), Icahn School of Medicine at Mount Sinai (US)
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