Key Points

  • Specific mutations, including TP53 and SF3B1, but not DNMT3A, TET2 and ASXL1, were enriched in older individuals with anemia.

  • Generally clones only confer a limited selective advantage over time, which is differentially affected by specific driver genes.

Anemia is a major and currently poorly understood clinical manifestation of hematopoietic ageing. Upon ageing, hematopoietic clones harboring acquired leukemia-associated mutations expand and become detectable, now referred to as clonal hematopoiesis (CH). To investigate the relationship between CH and anemia of the elderly we explored the landscape and dynamics of CH in older anemic individuals. From the prospective population-based Lifelines cohort (n=167.729), we selected all individuals ≥60 years with anemia according to WHO criteria (n=676) and 1:1 matched controls. Peripheral blood of 1298 individuals was analyzed for acquired mutations at ≥1% variant allele frequency (VAF) in 27 driver genes. To track clonal evolution over time, we included all available follow-up samples (n=943). CH was more frequently detected in anemic individuals (46.6%) compared to controls (39.1%) (P=0.007). Although no differences were observed regarding commonly detected DTA mutations (DNMT3A, TET2, ASXL1) in anemic individuals compared to controls, other mutations were enriched in the anemia cohort, including TP53 and SF3B1. Unlike individuals with nutrient deficiency (P=0.84), individuals with anemia of chronic inflammation and unexplained anemia revealed a higher prevalence of CH (P=0.035 and P=0.017 respectively) compared to their matched controls. Follow-up analyses revealed that clones may expand and decline, generally showing only a subtle increase in VAF over 44 months (mean 0.56%), irrespective of the presence of anemia. Specific mutations associated with different growth rates and propensities to acquire an additional hit. In contrast to smaller clones (<5% VAF) which did not affect overall survival, larger clones associated with increased risk of death.

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