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2545 Dynamics of Clonal Hematopoiesis Inferred By Modelling Deep Bulk Whole-Genome Sequencing Data at a Single Time Point

Program: Oral and Poster Abstracts
Session: 503. Clonal Hematopoiesis, Aging and Inflammation: Poster II
Hematology Disease Topics & Pathways:
adult, Fundamental Science, Research, elderly, CHIP, Translational Research, genomics, hematopoiesis, Biological Processes, Technology and Procedures, Human, Study Population
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Naser Ansari-Pour, PhD1*, Verena Körber, PhD2*, Niels Asger Jakobsen, BM BCh MRCP3*, Rachel Moore, BA3*, Nina Claudino2*, Marlen Metzner, MSc3*, Batchimeg Usukhbayar3*, Mirian Angulo Salazar, MSc3*, Simon Newman4*, Benjamin Kendrick4*, Adrian Taylor4*, Rasheed Afinowi-Luitz5*, Roger Gundle4*, Bridget Watkins4*, Kim Wheway4*, Debra Beazley4*, Andrew Carr, ChM DSc FRCS FMedSci4*, Paresh Vyas, DPhil, FRCP, FRCPath, MRCP, MRCPath1 and Thomas Höfer, PhD2*

1MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
2Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
3MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
4Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, United Kingdom
5Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom

Clonal hematopoiesis (CH) in the elderly is associated with increased risk for a variety of diseases, including myeloid malignancies. However, as not all CH subjects develop myeloid malignancy, there is heterogeneity in clinical outcome. Indeed, longitudinal studies over several years have shown that clonal growth rates vary considerably between individual cases, even for the same CH driver mutation. In particular, with increasing age, clones may become large not only by positive selection, but also stochastically through neutral drift. Thus, personalized diagnostics are needed to evaluate evolution of CH.

We analyzed the dynamics of normal and clonal hematopoiesis in twenty-one individuals with driver mutations in clonal hematopoiesis (CH)-associated genes and ten normal controls. To this end, we devised a population genetics model that learns the dynamics of normal and clonal hematopoiesis from the somatic variant allele frequency distribution in a single-patient bulk tissue sample. Moreover, the model can distinguish between drift and selection, both of which lead to somatic mosaicism but with different consequences for clonal evolution. To calibrate our model on human hematopoiesis, we identified somatic variants from deep (90X) whole-genome sequencing (WGS) of bulk bone marrow samples from our cohort and thereafter learned the model parameters using approximate Bayesian computation.

We found that clones with CH driver mutations originate decades before they are detected and confirmed these results using an independent approach that is based on CpG>TpG molecular clock timing. Thereafter, they expand due to positive selection rather than drift, with a selective advantage corresponding to a median growth rate of 26% per year in clones with a VAF of greater than 5%. While the selective advantage varied substantially between individuals, on average, DNMT3A variants conferred the strongest advantage, followed by TET2 and then ASXL1. By contrast, we did not detect a clear signal for clonal selection in bone marrow samples lacking known CH drivers. Remarkably, even CH clones with large advantage and growing over several decades did not make up the entire bone marrow in any of the analyzed individuals suggesting these clones grow with non-linear rates.

In summary, we provide a time-efficient and cost-effective method to study clonal dynamics of hematopoiesis at a large scale, which, by reducing cost and time, democratizes the research of somatic mosaicism and can be applied to other tissues. In addition, given that this method can reliably estimate clonal dynamics parameters such as time of initiation and growth rate, it may well serve current efforts in early detection of people at high risk for aggressive malignancy resulting from rapid clonal growth in a personalized medicine setting.

Disclosures: Vyas: Astellas: Honoraria; Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Bristol Myers Squibb: Research Funding; Daiichi Sankyo: Honoraria; JAZZ: Honoraria; Pfizer: Honoraria.

*signifies non-member of ASH