3104 – FITNESS IS A BETTER PREDICTOR OF OUTCOMES IN CLONAL HEMOPOIESIS COMPARED TO CLONE SIZE

• Published in: Experimental hematology 2024-08, Vol.137, p.104426, Article 104426
• Main Authors: Kirschner, Kristina, Chandra, Tamir, Cox, Simon, Deary, Ian, Harris, Sarah, Kosebent, Esra Gozde, Latorre-Crespo, Eric, Murphy, Lee, Schumacher, Linus, Robretson, Neil
• Format: Article
• Language: English
• ISSN: 0301-472X
• DOI: 10.1016/j.exphem.2024.104426

The prevalence of clonal haematopoiesis of indeterminate potential (CHIP) in healthy individuals increases rapidly from age 60 onwards and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in stem cells that are also drivers of myeloid malignancies. We previously set out to quantify the fitness effects of CHIP drivers over a 12-year timespan in older age, using longitudinal error-corrected sequencing data. We now extended our longitudinal data to include participants from two other longitudinal cohorts of aging. We show that fitness is a better predictor of all-cause mortality compared to clone size. Moreover, we generated a tool to allow for deconvolution of clonal complexities in the blood of aged individual, highlighting clonal composition and co-occurrence of mutations. We identified commonly co-occurring mutations with older age and will discuss consequences of those co-occurring mutations. In summary, longitudinal cohorts allow identification of clonal evolution in individuals with advanced age.