Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects

Robertson, N. A. et al. (2022) Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects. Nature Medicine, 28(7), pp. 1439-1446. (doi: 10.1038/s41591-022-01883-3) (PMID:35788175) (PMCID:PMC9307482)

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Clonal hematopoiesis of indeterminate potential (CHIP) increases rapidly in prevalence beyond age 60 and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in hematopoietic stem and progenitor cells (HSPCs). Because mutations in HSPCs often drive leukemia, we hypothesized that HSPC fitness substantially contributes to transformation from CHIP to leukemia. HSPC fitness is defined as the proliferative advantage over cells carrying no or only neutral mutations. If mutations in different genes lead to distinct fitness advantages, this could enable patient stratification. We quantified the fitness effects of mutations over 12 years in older age using longitudinal sequencing and developed a filtering method that considers individual mutational context alongside mutation co-occurrence to quantify the growth potential of variants within individuals. We found that gene-specific fitness differences can outweigh inter-individual variation and, therefore, could form the basis for personalized clinical management.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Terradas Terradas, Maria and Copland, Professor Mhairi and Robertson, Mr Neil and Livesey, Benjamin and Lemos Portela, Jorge and Kirschner, Dr Kristina
Authors: Robertson, N. A., Latorre-Crespo, E., Terradas-Terradas, M., Lemos-Portela, J., Purcell, A. C., Livesey, B. J., Hillary, R. F., Murphy, L., Fawkes, A., MacGillivray, L., Copland, M., Marioni, R. E., Marsh, J. A., Harris, S. E., Cox, S. R., Deary, I. J., Schumacher, L. J., Kirschner, K., and Chandra, T.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Nature Medicine
Publisher:Nature Research
ISSN (Online):1546-170X
Published Online:04 July 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Nature Medicine 28(7): 1439-1446
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
306709Early detection of pre-leukaemic clones in the aged haematopoietic compartment using single cell approachesKristina KirschnerLeukaemia UK (LEUKA)2019/JGF/003CS - Epigenetics
174115CRUK Centre RenewalOwen SansomCancer Research UK (CRUK)C7932/A25142CS - Beatson Institute for Cancer Research
304005MRC Precision Medicine Training GrantMorven BarlassMedical Research Council (MRC)MR/N013166/1-LGH/MS/MED25CAMS - Cardiovascular Science