Factors Influencing the Somatic Mutational Landscape of Ageing Squamous Epithelium

The incidences of many cancers vary substantially across the world, reflecting genetic differences between populations and exposure to environmental carcinogens. This is illustrated by keratinocyte skin cancers and oesophageal squamous cell carcinoma, which both develop from squamous epithelium, yet are remodelled during ageing by very different mutagenic processes and environmental exposures. In this thesis, I investigate the influence of cancer risk factors on the somatic mutations present in normal aged skin and oesophageal epithelium using a range of sequencing methods. I find sun-exposed facial skin from donors of the UK to have a 4-fold increased mutation burden and 10-fold increase in copy number aberrant clones compared to donors of Singapore, a country with a 17-fold lower incidence of keratinocyte skin cancer. The majority of these mutations in the UK are due to ultraviolet radiation (UV) but, in Singapore, age-related signatures predominate. Mutations in TP53 are more strongly selected in epidermis of the UK, whilst those in NOTCH1 and NOTCH2 are preferentially selected in Singapore, reflecting differences in the level of competition within the tissue. A survey of mutations in UK skin across body sites reveals differences in UV signature and selection between sites. In aged oesophageal epithelium from UK donors, I observe an increase in mutations with an alcohol-associated signature with reported alcohol consumption. Furthermore, mutation burden increases with smoking, without a detectable change in the mutational signature, consistent with tobacco smoke increasing oesophageal cancer risk independent of its mutagenic effects. Finally, in donors over the age of 60, mutations in TP53 and FAT1 are more strongly selected, whilst those in NOTCH3 more weakly selected, suggesting changes to levels of competition within the tissue with age. I conclude that the mutational landscapes of normal oesophagus and skin are shaped by age and environmental exposures and that this, in turn, may alter the risk of keratinocyte cancers.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2022

Author dc:creator

• King, Charlotte

Advisor dc:contributor.advisor

• Jones, Phil

• somatic mutation
• squamous epithelium
• clonal selection
• squamous cell carcinoma
• keratinocyte
• oesophagus
• skin
• normal tissue

Licence

• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.90348

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/342936