Identifying new targets for cancer prevention and therapy by linking common exposures or cancer risk factors to tumour molecular mechanisms

Abstract

Studies of the germline and somatic tumour genomes have independently advanced our understanding of cancer development, informing strategies for prevention and treatment. However, these domains have traditionally been studied in isolation, limiting mechanistic insights underlying cancer biology. This thesis addresses this gap by leveraging germline and somatic multi-omic data to identify cancer risk factors and tumour molecular mechanisms.

Chapter 1 introduces the background and overarching aims of this thesis.

Chapter 2 leverages matched germline and somatic tumour multi-omic data from The Cancer Genome Atlas to investigate the molecular landscape of solid tumours. In Chapter 2, I show that endometrial cancers developed on a germline genetic background of elevated body mass index exhibit distinct genomic, transcriptomic, proteomic and immune alterations. These findings provide mechanistic insights linking excessive adiposity with endometrial cancer development.

Chapters 3-5 focus on pre-leukaemic clonal haematopoiesis (CH), the clonal expansion of haematopoietic stem and progenitor cells harbouring somatic fitness-enhancing mutations. In Chapters 3-4, I use Mendelian randomisation to evaluate evidence for the causal effects of modifiable endogenous and exogenous exposures on CH risk, highlighting potential targets for CH prevention. In Chapter 5, I conduct a multi-trait genome-wide association study of CH risk, integrating summary statistics from blood cell traits to improve statistical power and identify new germline risk loci for CH, informing potential strategies for risk stratification.

Chapter 6 summarises the key findings from Chapters 2-5, emphasising how germline-somatic studies can enhance understanding of cancer biology and molecular mechanisms informing translational opportunities for cancer prevention and risk stratification.

Date of Award	20 Jan 2026
Original language	English
Awarding Institution	University of Bristol
Supervisor	Siddhartha P. Kar (Supervisor), Emma E Vincent (Supervisor), Caroline L Relton (Supervisor) & Tom R Gaunt (Supervisor)