Clinical progression of clonal hematopoiesis is determined by a combination of mutation timing, fitness, and clonal structure
Year: 2025
Type: preprint
Study design: Observational Study
Abstract: Clonal hematopoiesis (CH) is characterized by expanding blood cell clones carrying somatic mutations in healthy aged individuals and is associated with various age-related diseases and all-cause mortality. While CH mutations affect diverse genes associated with myeloid malignancies, their mechanisms of expansion and disease associations remain poorly understood. We investigate the relationship between clonal fitness and clinical outcomes by integrating data from three longitudinal aging cohorts (n=713, observations=2,341). We demonstrate pathway-specific fitness advantage and clonal composition influence clonal dynamics. Further, the timing of mutation acquisition is necessary to determine the extent of clonal expansion reached during the host individual's lifetime. We introduce MACS120, a metric combining mutation context, timing, and variant fitness to predict future clonal growth, outperforming traditional variant allele frequency measurements in predicting clinical outcomes. Our unified analytical framework enables standardized clonal dynamics inference across cohorts, advancing our ability to predict and potentially intervene in CH-related pathologies.
Authors: Eric Latorre-Crespo, Neil A. Robertson, E. Gozde Kosebent, Louise MacGillivray, Lee Murphy, Mesbah Uddin, Eric Whitsel, Michael Honigberg, Alex Bick, Alexander P. Reiner, Valeria Orrù, Michele Marongiu, Francesco Cucca, Edoardo Fiorillo, Ian J. Deary, Sarah Harris, Simon Cox, Riccardo Marioni, Linus Schumacher, Tamir Chandra, Kristina Kirschner
Institutions: Centre de Recerca Matemàtica, Cancer Research UK Scotland Institute, University of Glasgow, Mayo Clinic, University of Edinburgh, Western General Hospital, Broad Institute, Massachusetts General Hospital, University of North Carolina at Chapel Hill, Mass General Brigham, Vanderbilt University, Vanderbilt University Medical Center, University of Washington, Fred Hutch Cancer Center, National Research Council, Institute of Genetics and Cancer, MRC Centre for Regenerative Medicine, Maxwell Institute for Mathematical Sciences
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4408093363