Abstract
dc:description.abstractEvery mitotic cell division runs the risk of incorporating genomic changes into the daughter cell lineages. From the very first zygotic cleavage to the maintenance of trillions of cells in adulthood, these somatic mutations are acquired throughout life either via endogenous errors in DNA replication or environmental DNA damage factors. Most of these somatic mutations land in the vast noncoding intergenic regions of the genome, marking cell lineage but having no effect on physiology. However, each new mutation also has a small chance of leading to pathogenesis, with particularly high stakes in development. Unlike potentially pathogenic mutations acquired later in life, prenatal mutations can hitchhike along developmental pathways to create large numbers of cells across many tissue types predisposed to genetic diseases like cancer. In this thesis, I present three vignettes focused on these developmental mutations, both using passenger somatic mutations as lineage markers of normal development and by uncovering their pathogenic potential as an underappreciated cause of paediatric malignancy. First, I use whole genome DNA and methylation sequencing of single cells derived from all germ layers to uncover the dynamics of early embryonic cell divisions in normal human development. Next, I turn my focus to two examples of developmental mutations leading to paediatric cancer. My second chapter unpicks the origin of infant acute lymphoblastic leukaemia, an aggressive disease with a prenatal aetiology. In the third chapter, I present a case study of a teenager with multifocal, multiphenotypic tumours driven by a driver mutation acquired in embryogenesis, highlighting how mosaic mutations can result in unique patterns of disease risk and phenotype. Altogether, my thesis highlights how developmental somatic mutations have power as tools to study development and also have the potential to drive disease. Integrating the evolutionary histories of cells with multiomic approaches can reveal great insight into the paths they take from embryonic to mature or healthy to diseased, with great potential impact for both biology and clinical care of patients.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2024
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Pacyna, Clarissa
- Advisors dc:contributor.advisor
-
- Campbell, Peter
- Mitchell, Thomas
Subjects
dc:subject × 3Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.119419
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/386015