-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

2745 Opposing Evolutionary Pressures Drive Clonal Evolution and Health Outcomes in the Aging Blood System

Program: Oral and Poster Abstracts
Session: 503. Clonal Hematopoiesis: Aging and Inflammation: Poster III
Hematology Disease Topics & Pathways:
AML, Diseases, Biological Processes, Myeloid Malignancies, genomics, hematopoiesis
Monday, December 7, 2020, 7:00 AM-3:30 PM

Kimberly Skead1,2*, Armande Ang Houle1,2*, Sagi Abelson, PhD1,2*, Marie-Julie Fave, PhD2*, Boxi Lin3*, David Soave, PhD2,4*, Stephen Wright, PhD5*, John E. Dick, PhD, FRS1,2,6, Quaid Morris, PhD1,2,7* and Phillip Awadalla, PhD1,2*

1Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
2Ontario Institute for Cancer Research, Toronto, ON, Canada
3Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
4Department of Mathematics, Wilfrid Laurier Univesity, Waterloo, ON, Canada
5Department of Ecology and Evolutionary Biology, University of Toronto, Toronto, ON, Canada
6Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, ON, Canada
7Computational & Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY

The age-associated accumulation of somatic mutations and large-scale structural variants (SVs) in the early hematopoietic hierarchy have been linked to premalignant stages for cancer and cardiovascular disease (CVD). However, only a small proportion of individuals harboring these mutations progress to disease, and mechanisms driving the transformation to malignancy remains unclear. Hematopoietic evolution, and cancer evolution more broadly, has largely been studied through a lens of adaptive evolution and the contribution of functionally neutral or mildly damaging mutations to early disease-associated clonal expansions has not been well characterised despite comprising the majority of the mutational burden in healthy or tumoural tissues. Through combining deep learning with population genetics, we interrogate the hematopoietic system to capture signatures of selection acting in healthy and pre-cancerous blood populations. Here, we leverage high-coverage sequencing data from healthy and pre-cancerous individuals from the European Prospective Investigation into Cancer and Nutrition Study (n=477) and dense genotyping from the Canadian Partnership for Tomorrow’s Health (n=5,000) to show that blood rejects the paradigm of strictly adaptive or neutral evolution and is subject to pervasive negative selection. We observe clear age associations across hematopoietic populations and the dominant class of selection driving evolutionary dynamics acting at an individual level. We find that both the location and ratio of passenger to driver mutations are critical in determining if positive selection acting on driver mutations is able to overwhelm regulated hematopoiesis and allow clones harbouring disease-predisposing mutations to rise to dominance. Certain genes are enriched for passenger mutations in healthy individuals fitting purifying models of evolution, suggesting that the presence of passenger mutations in a subset of genes might confer a protective role against disease-predisposing clonal expansions. Finally, we find that the density of gene disruption events with known pathogenic associations in somatic SVs impacts the frequency at which the SV segregates in the population with variants displaying higher gene disruption density segregating at lower frequencies. Understanding how blood evolves towards malignancy will allow us to capture cancer in its earliest stages and identify events initiating departures from healthy blood evolution. Further, as the majority of mutations are passengers, studying their contribution to tumorigenesis, will unveil novel therapeutic targets thus enabling us to better understand patterns of clonal evolution in order to diagnose and treat disease in its infancy.

Disclosures: Dick: Bristol-Myers Squibb/Celgene: Research Funding.

*signifies non-member of ASH