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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Abstract
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 |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| 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: | 1078-8956 |
| 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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