Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults

Abstract

Clonal haematopoiesis is thought to be a rare condition that increases in frequency with age and predisposes individuals to haematological malignancy. Recent studies, utilizing next-generation sequencing (NGS), observed haematopoietic clones in 10% of 70-year olds and rarely in younger individuals. However, these studies could only detect common haematopoietic clones—>0.02 variant allele fraction (VAF)—due to the error rate of NGS. To identify and characterize clonal mutations below this threshold, here we develop methods for targeted error-corrected sequencing, which enable the accurate detection of clonal mutations as rare as 0.0003 VAF. We apply these methods to study serially banked peripheral blood samples from healthy 50–60-year-old participants in the Nurses' Health Study. We observe clonal haematopoiesis, frequently harbouring mutations in DNMT3A and TET2, in 95% of individuals studied. These clonal mutations are often stable longitudinally and present in multiple haematopoietic compartments, suggesting a long-lived haematopoietic stem and progenitor cell of origin.

JAK2 V617F hematopoietic clones are present several years prior to MPN diagnosis and follow different expansion kinetics

“…14 A recent study used ultrasensitive sequencing to show that clonal hematopoiesis driven by acute myeloid leukemia (AML)-associated mutations was ubiquitous among healthy adults aged 50 to 60 years. 15 Interestingly, most clones identified in this study were associated with loss-of-function mutations in DNMT3A and TET2, and although most persisted over long periods (.10 years), they usually exhibited only modest expansion if any. However, in contrast to studies looking at larger numbers of people with lower assay sensitivities, 6-9 this study did not identify JAK2 mutant clones in any of its 20 participants.…”

“…However, in contrast to studies looking at larger numbers of people with lower assay sensitivities, 6-9 this study did not identify JAK2 mutant clones in any of its 20 participants. 15 It is therefore possible that JAK2 V617F, a hot spot mutation that relies on a G.T transversion that is uncommon in myeloid malignancies, 16 is acquired less often but has a more pronounced effect on clonal growth than many other mutations. Nevertheless, it should be noted that the high rates of clonal growth in our study were observed in individuals that (1) were younger than the average MPN patient (as they were identified because they were registered stem cell donors) and (2) did actually go on to develop MPN and are therefore unlikely to be characteristic of the general behavior of JAK2 V617F clones.…”

Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly

“…We note in passing that under this model, none of the low-VAF CD mutations reported by Young et al 23 could have generated a case that meets our criteria for CH.…”

“…[19][20][21][22][23] Until now, this has precluded formal tests of association between CD mutations and CH. In this study we use the observation that HSCs accumulate somatic mutations during their life history, most of which have no apparent effect on cellular phenotype.…”

Prevalent premalignancy

“…The use of ultradeep, error-corrected sequencing has previously demonstrated mutations within DNMT3A or TET2 in up to 95% of older adults, suggesting that if you sequence deeply enough you can find a mutant clone in virtually all subjects. 10 The most common recurrently mutated genes identified by Buscarlet et al are also DNMT3A and TET2, and these 2 genes account for a somewhat larger proportion (93%) of all mutations than in previous reports. 6,7 They further assess the relationship between these mutations and a variety of hematological parameters, demonstrating no significant correlation between mutation status and any abnormality in the blood.…”