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. 2016 Aug 22:7:12484.
doi: 10.1038/ncomms12484.

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

Andrew L Young  1   2 , Grant A Challen  3 , Brenda M Birmann  4 , Todd E Druley  1   2
Affiliations

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

Andrew L Young et al. Nat Commun. .

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.

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Figures

Figure 1
Figure 1. Number and characteristics of clonal SNVs detected by ECS in the peripheral blood of healthy adult nurses.
(a) Clonal SNVs detected in each individual, colour-coded by annotation. (b) Exonic clonal SNVs detected in each individual, colour-coded by predicted effect. (c) Detected exonic clonal SNVs organized by gene, colour-coded by predicted effect. (d) Distribution of substitution types observed in clonal SNVs.
Figure 2
Figure 2. Longitudinal detection of clonal SNVs in NHS participants.
Clonal SNVs were detected by ECS in both time points for 16/20 NHS participants. For each participant ID (PID), the VAF measured by ECS was plotted relative to the age at sample collection. Variants detected in both time points were connected with a line.
Figure 3
Figure 3. Haematopoietic compartment-specific detection of clonal SNVs in NHS participants.
Paired buffy coat samples from 13 individuals were sorted into B lymphocyte (pink), T lymphocyte (purple) and myeloid (blue) compartments using flow cytometry. For each NHS participant ID (PID), a single SNV, detected by ECS, was selected for compartment-specific quantification by ddPCR. Variants detected in both time points were connected with a line. The VAF measured by ddPCR in the bulk sample (green) was included for comparison.
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