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The natural history of clonal haematopoiesis


Type

Thesis

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Authors

Fabre, Margarete 

Abstract

Introduction Human cells acquire somatic mutations throughout life, some of which can drive clonal expansion. Such expansions are frequent in the haematopoietic system of healthy individuals and have been termed clonal haematopoiesis (CH). While CH predisposes to myeloid neoplasia and other diseases, we have limited understanding of its natural history and how this relates to clinical phenotype.

Objectives

  1. To characterise the behaviour of CH across the human lifespan;
  2. To identify and quantify determinants of clonal behaviour;
  3. To understand how CH clonal dynamics relate to malignant progression.

Results By tracking 697 CH clones from 385 individuals aged 55 or older over a median of 13 years, we found that 92.4% of clones expanded at a stable exponential rate in old age, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A, TP53) to over 50%/yr (SRSF2-P95H). Growth rates of clones with the same mutation differed by +/-5%/yr, proportionately impacting “slow” drivers more substantially. Combining these time-series data with phylogenetic analysis of 1,731 whole genome-sequenced haematopoietic colonies from 7 older individuals revealed 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 only drove expansion later in life, while TET2-mutant clones emerged across all ages. Using a separate cohort of 158 twins, we found that concordance for CH was no higher within monozygotic vs dizygotic pairs, suggesting that the inherited genome does not exert a dominant influence on CH behaviour. The identification of two monozygotic pairs in which both twins harboured identical rare somatic mutations confirmed that the origins of adult CH can be traced back to early life, even in utero. Finally, by comparing CH growth dynamics with (i) driver mutation selection patterns in large myeloid cancer data sets and (ii) driver-specific AML risk scores, we show that mutations driving faster clonal growth also carry a higher risk of malignant progression.

Conclusions These findings characterise the origins and lifelong natural history of CH and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.

Description

Date

2022-05-01

Advisors

Vassiliou, George

Keywords

ageing, cancer, clonal dynamics, clonal haematopoiesis, stem cells

Qualification

Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge