Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-020-20565-7
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Funding
- National Institute of Health [K08CA241318, P30 CA008748, UG1-HL069315, F31 CA254130-01]
- American Society of Hematology
- EvansMDS Foundation
- European Hematology Association
- Gabrielle's Angels Foundation
- V Foundation
- Geoffrey Beene Foundation
- Cycle for Survival
- Starr Cancer Consortium
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This study jointly characterized gene mutations and mCAs in clonal hematopoiesis using peripheral blood sequencing data from cancer patients. Patients with composite genotypes in clonal hematopoiesis were found to have a higher risk of leukemia progression, with mCA identified as an independent risk factor for leukemia development.
Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations (n = 14,789) and mCAs (n = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7-22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6-33, P < 0.001). Our results suggest that mCA should be considered in conjunction with gene mutations in the surveillance of patients at risk of hematologic neoplasms.
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