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Somatic mutagenesis in humans with deficient DNA repair


Type

Thesis

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Authors

Robinson, Philip S 

Abstract

The accumulation of mutations in normal cells causes the development of cancer and is implicated as a potential mechanism in the physiological process of ageing. In recent years our ability to interrogate the genome of human cancers and the normal tissues from which they arise has expanded greatly. These studies have shown that mutations accumulate in normal tissues throughout life and that mutation rates are remarkably similar across individuals. However, the potential impact of increased somatic mutation rates on the risk of developing cancer and the process of ageing is not known.

In this thesis, two inherited syndromes associated with intestinal cancer predisposition were selected to investigate the mutation burdens and mutational processes across different normal tissue types. Individuals with these syndromes have a known elevated risk of cancer which is thought to be underpinned by an increased somatic mutation rate. Chapter 3 summarises experiments that investigate somatic mutagenesis in a selection of normal tissue types from individuals with germline heterozygous mutations in the DNA polymerase genes POLE and POLD1. Chapter 4 summarises the investigation of somatic mutagenesis in normal tissues from individuals with germline MUTYH mutations. In Chapter 5 findings from the two cancer predisposition syndromes are compared and the results are placed in the broader context of intestinal cancer predisposition syndromes. Lastly, the observations from this thesis are interpreted with regards our current understanding of the somatic mutation theory of ageing.

In summary, this thesis presents insight into somatic mutagenesis in normal tissues from individuals with known cancer predisposition. The findings may have potential implications for our understanding of cancer risk in predisposed and non-predisposed individuals. The observation of increased somatic mutation rates in normal healthy tissues also has pertinence to our understanding of the somatic mutation theory of ageing. The data presented in the thesis serve as a potential proof-of-concept for the measurement of somatic mutagenesis in normal tissues to improve the care of individuals with inherited DNA repair defects.

Description

Date

2022-02-01

Advisors

Stratton, Michael R
Campbell, Peter

Keywords

somatic mutagenesis, ageing, cancer, mutational processes, intestinal polyposis, inherited cancer predisposition

Qualification

Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
Sponsorship
Wellcome Clinical PhD Fellowship