The longitudinal dynamics and natural history of clonal haematopoiesis

Abstract

Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis1–4. The understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited5,6. Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A and TP53) to more than 50% per year (SRSF2P95H). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2-mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.

Frequent whole blood donations select for DNMT3A variants mediating enhanced response to erythropoietin

“…The VAF of the majority of DNMT3A mutations did not change between the two time points analyzed (Figures 2E-F). This is consistent with a recent report demonstrating rapid expansion of DNMT3A -mutant clones early, but rather slow growth later in life 51 . Nevertheless, within the frequent donor cohort, 4 out of 16 DNMT3A mutations analyzed displayed a 1.5-3-fold increase in their VAF (Figure 2E and Supplemental Table 6).…”

“…Accordingly, our analysis of consecutive samples confirmed that the VAF of the majority of DNMT3A mutations remains stable. This is consistent with a recent long-term follow-up study showing that DNMT3A mutations are more likely to expand early in life and display a slower growth in older age 51 . The current paradigm in the field is that specific cues from the environment are necessary to favor the outgrowth of HSPCs carrying mutations they acquire during the course of life 24,25,51,63 .…”

“…The only TET2 mutation from the CD showed a similar VAF at the second timepoint (Figure 2G). In line with this, TET2 mutated clones have previously been demonstrated to grow uniformly across ages 51 .…”

Mutation rates and fitness consequences of mosaic chromosomal alterations in blood

“…Third, the fitness effect of a mutation could itself be dependent on genotype and age. A recent study has reported DNMT3A mutant clones whose fitness advantage decreases with age ( 7 ). If such an effect existed for mCAs it would be expected to produce weaker age dependence.…”

“…Mutations in haematopoietic stem and progenitor cells (HSPCs) which confer a 'Darwinian' fitness advantage can clonally expand to detectable levels in blood -a phenomenon known as clonal haematopoiesis (CH) (1)(2)(3)(4). Previous studies have developed population genetic frameworks for estimating the mutation rates and associated fitness effects of these mutations (5,6) and these estimates have been validated in subsequent studies leveraging serial sampling (7) and single-cell derived phylogenies (8). These previous analyses have largely focused on the fitness effects and mutation rates of single nucleotide variants (SNVs) in cancer-associated genes.…”