Wellcome GW4 Clinical Academic Training PhD Fellowship: Using genetics to explore the effects of metabolic traits in head and neck cancer.

Given the significant decline in smoking rates, particularly within developing countries, other potentially modifiable risk factors for head and neck cancer (HNC) warrant investigation. Obesity and related metabolic disorders such as type 2 diabetes, hypertension and dyslipidaemia have all been associated with HNC risk in multiple observational studies.

Epidemiological evidence also suggests that statins (and other cholesterol-lowering therapies) may be protective against HNC. However, bias, confounding or reverse causality could explain these findings.

This thesis aims to appraise the causal effect of metabolic traits and cholesterol-lowering
therapies on HNC risk using Mendelian randomization (MR), triangulated with observational and experimental evidence where possible.

In Chapter 1, I define the disease and metabolic trait exposures to be investigated. Chapter 2 provides an overview of the changing epidemiology of HNC, including the characteristics of the disease and biological mechanisms linking metabolic traits and cancer. In Chapter 3, the assumptions, strengths and weaknesses of MR are evaluated, in particular when investigating HNC as an outcome. In Chapter 4, a comprehensive systematic review and meta-analysis of observational studies finds increased risk associations for hypertension and dyslipidaemia.

This is further tested using MR in Chapter 5, where limited evidence is found for any effect of metabolic traits on oral and oropharyngeal cancer risk, suggesting the presence of residual confounding in observational estimates. However, small effects cannot be excluded and replication using better powered GWAS is required. Chapter 6 uncovers an adverse effect of cholesterol lowering via genetically-proxied PCSK9 inhibition on oropharyngeal cancer risk. However, experimental follow-up to further characterise PCSK9 in oropharyngeal cancer (Chapter 7) fails to show a clear role for this gene in tumour cell proliferation or viral entry, indicating a need for further research. Chapter 8 summarises the thesis findings, which overall do not support prioritising metabolic traits in prevention strategies for HNC.