Phylogenetic studies into the development of foetal tissues and their neoplastic derivatives

Over a lifetime, each cell in the human body acquires a unique combination of somatic mutations that encode its ancestry, exposure to mutagens and strategy for optimising survival. Studies into normal and neoplastic tissues in adults have delineated clonal architecture and oncogenesis at an exquisite resolution. However, for over a century, data have indicated that childhood cancer is rather different, most likely emerging as an aberration of foetal development. This thesis explores how foetal tissues and their neoplastic progeny propagate, focusing specifically on the placenta, germ cell tumours and high-grade midline gliomas. In Chapter 1, I introduce the principles and technological advances that allow us to infer development from somatic mutations. I highlight existing evidence for the distinct origins of childhood and adult cancers and discuss the unique mutational forces that prenatal cells endure. Applying whole genome sequencing (WGS) to bulk and microdissected placental tissues, I begin my own lines of enquiry in Chapter 2. I show that placental trophoblast is unique amongst normal tissues in its clonal construction and sustains a pattern and rate of mutation normally seen in cancer. Each placental biopsy represents a driverless expansion of a spatially-fixed early embryonic precursor, making the placenta inherently mosaic. I turn my attention to neoplasia in Chapters 3 and 4. Using WGS from bulk and microdissected germ cell tumours in Chapter 3, I detail differences in cancer genomes by age group, including their mutational exposures. Where tumours form many, apparently normal tissues, RNA sequencing captures underlying foetal transcriptional signals and diversity that cannot be explained by mutation. In Chapter 4, I outline my work using WGS from post-mortem normal and neoplastic tissues of three children with high-grade midline gliomas. Germline *NF1* mutation is associated with independent, second *NF1* hits that pervade the macro- and microscopically unremarkable brain and spinal cord. Each glioma is characterised by abundant subclonal drivers with different lineages mutating the same genes recurrently, possibly exacerbated by radiotherapy. I conclude in Chapter 5 by exploring the clinical and histopathological utility of these types of experiments and considering new studies to gauge the impact of mutation on organogenesis. Lastly, I highlight other areas of child health where study of somatic mutation may prove beneficial.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Oliver, Thomas

Advisors dc:contributor.advisor

• Behjati, Sam
• Rahbari, Raheleh

• Germ cell tumour
• High-grade glioma
• Neurofibromatosis type 1
• Placenta
• Somatic mutation

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/7ac236e2-67c6-4ccf-be55-2018f06d5518/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.105518

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/363461