Every year, over 360,000 people in the UK are diagnosed with cancer and around 160,000 die as a result of the disease. Cancer costs the NHS over £5 billion annually, while the loss of human productivity due to cancer in the UK is estimated to be £18 billion a year. Above all, cancer impacts patients and their families in ways that are beyond measure. This makes cancer one of the most pressing societal challenges of this century. Cancer is a disease of the genome. Certain changes that are acquired over the course of life in the genomes of healthy cells in the human body (somatic genomic changes) dysregulate the fine balance between cell death and proliferation. These somatic genomic aberrations are the cornerstone of malignant cellular transformation. Targeting somatic genomic changes is fundamental to the practice of precision cancer medicine. We understand that common exposures and cancer risk factors such as ultraviolet light and smoking accelerate the acquisition of these changes. However, little is actually known about how everyday exogeneous and endogenous factors such as diet, obesity, and insulin resistance relate to, and likely drive, carcinogenic changes in the somatic genome. This is because it is difficult to measure lifelong trajectories of the factors retrospectively at cancer diagnosis and expensive to measure them prospectively in large numbers of individuals until some of them develop cancer. Such one-time "snapshot" measures, even where feasible, are prone to bias and confounding. Specific inherited or germline genetic variants have been found to be robustly associated with these exposures or factors. Since genetic variants are allocated at random at conception and fixed thereafter, they are less affected by bias and confounding. The factor-associated variants provide remarkable proxies for the lifetime levels of these factors even in patients in whom the factor itself has not been measured. These variants collected into polygenic scores serve as instruments in Mendelian randomisation (MR) studies that evaluate association between the germline genetically-inferred levels of the factor and a disease outcome. MR studies of cancer have so far been limited to an appraisal of the relationship between putative risk factors and cancer risk. The crucial conceptual advances being proposed here are the application of an MR-like approach to identify somatic/tumour molecular changes that operate within the cancer and are associated with factors such as obesity and the illumination of the role of the identified tumour molecular changes in driving cancer progression and response to cancer drugs. This novel shift in the conventional MR paradigm is challenging to accomplish but has dramatic potential for translational clinical impact. First, by testing for association between a comprehensive range of potentially modifiable everyday exposures and specific somatic genetic mechanisms on the pathway to cancer, the proposed research will generate a rich catalogue of precise molecular targets for further preventive intervention. The availability of a target would mean that such intervention could go beyond policies aimed at influencing behaviour and take the form of primary chemoprevention for high-risk populations. Second, these molecular targets with a clear and well-reasoned link to common exposures may serve as biomarkers for early detection and in the diagnostic or prognostic classification of cancer. Third, untangling the complex interplay between extrinsic/intrinsic exposures and the somatic genome and establishing the sequence of events from exposure to pre-malignancy to cancer may inform strategies for rational anti-tumour therapeutic development. An exhaustive set of tumour molecular changes will be evaluated but a particular focus will be on mutational signatures and anti-tumour immune cell infiltrate signatures, given that these may determine response to chemotherapy, and targeted and immuno-oncology treatments.

Esophageal cancer is the third most common cancer and cause of cancer death in both men and women in Kenya, with 3000+ newly diagnosed patients in 2012. This pattern is common to other East African countries and West Kenya appears to have extremely high rates of the disease. This status contrasts to much of West Africa where the cancer is extremely rare, i.e. 40 times lower. Sadly, the majority of these patients pass away within 6 months of their diagnosis, few being able to afford the limited treatment options. Additionally, up to 15% of patients are very young, in their 20s and 30s. Despite researchers having known about this unusual disease pattern since the 1950s, the risk factors for the disease had hardly been studied prior to 2014. Consequently, there are no targeted strategies to prevent the disease, and no prediction models to identify who might be at high risk of the disease, people whom may benefit from early detection. In 2014, we - i.e. the Kenya PI Dr Diana Menya of Moi University, Eldoret - commenced the first comprehensive study of lifestyle, environmental and genetic factors for esophageal cancer in Kenya. The study was conducted at the Moi Teaching and Referral Hospital, Eldoret, which serves a catchment population stretching to the Ugandan border. In the study, patients newly diagnosed with esophageal cancer were compared to hospital patients and hospital visitors who did not have the disease. The study blood and tumour samples were also collected for genetic analyses. Results from the study have shown that alcohol and tobacco contribute to the disease in older men, but not in women or in young patients, a knowledge gap which the present study hopes to fill through a UK-Kenya collaboration between Dr Menya and Dr Daniel Pope, a household air pollution expert from the University of Liverpool. This study hypothesizes that household air pollution, from using biomass for cooking in poorly ventilated kitchens, is a large contributor to esophageal cancer in the young and in women, through traditional domestic roles associated with cooking. Household air pollution from biomass and coal use is already an established lung carcinogen, but few studies have examined its influence on esophageal cancer. However, work in an Iranian area of high esophageal cancer rates has shown that chemical compounds formed after combustion of biomass fuels are implicated in esophageal cancer risk in that setting. In this UK-Kenya collaboration, we propose to continue the core study as previously successfully implemented, and add to it an in-depth component on household air pollution as measured in kitchens and for personal exposures during household visits to a subset of female and younger (< 40 years) participants who live within reach of the referral hospital. A detailed analysis of oesophageal cancer risk with household air pollution will be provided and finally, considering a range of lifestyle and environmental risk factors, a comprehensive report on the strategies needed for primary prevention esophageal cancer in Kenya will be developed. Rates of this disease have declined in many areas of the world - Kenya should be able to follow this trend.

Every year, over 360,000 people in the UK are diagnosed with cancer and around 160,000 die as a result of the disease. Cancer costs the NHS over £5 billion annually, while the loss of human productivity due to cancer in the UK is estimated to be £18 billion a year. Above all, cancer impacts patients and their families in ways that are beyond measure. This makes cancer one of the most pressing societal challenges of this century. Cancer is a disease of the genome. Certain changes that are acquired over the course of life in the genomes of healthy cells in the human body (somatic genomic changes) dysregulate the fine balance between cell death and proliferation. These somatic genomic aberrations are the cornerstone of malignant cellular transformation. Targeting somatic genomic changes is fundamental to the practice of precision cancer medicine. We understand that common exposures and cancer risk factors such as ultraviolet light and smoking accelerate the acquisition of these changes. However, little is actually known about how everyday exogeneous and endogenous factors such as diet, obesity, and insulin resistance relate to, and likely drive, carcinogenic changes in the somatic genome. This is because it is difficult to measure lifelong trajectories of the factors retrospectively at cancer diagnosis and expensive to measure them prospectively in large numbers of individuals until some of them develop cancer. Such one-time "snapshot" measures, even where feasible, are prone to bias and confounding. Specific inherited or germline genetic variants have been found to be robustly associated with these exposures or factors. Since genetic variants are allocated at random at conception and fixed thereafter, they are less affected by bias and confounding. The factor-associated variants provide remarkable proxies for the lifetime levels of these factors even in patients in whom the factor itself has not been measured. These variants collected into polygenic scores serve as instruments in Mendelian randomisation (MR) studies that evaluate association between the germline genetically-inferred levels of the factor and a disease outcome. MR studies of cancer have so far been limited to an appraisal of the relationship between putative risk factors and cancer risk. The crucial conceptual advances being proposed here are the application of an MR-like approach to identify somatic/tumour molecular changes that operate within the cancer and are associated with factors such as obesity and the illumination of the role of the identified tumour molecular changes in driving cancer progression and response to cancer drugs. This novel shift in the conventional MR paradigm is challenging to accomplish but has dramatic potential for translational clinical impact. First, by testing for association between a comprehensive range of potentially modifiable everyday exposures and specific somatic genetic mechanisms on the pathway to cancer, the proposed research will generate a rich catalogue of precise molecular targets for further preventive intervention. The availability of a target would mean that such intervention could go beyond policies aimed at influencing behaviour and take the form of primary chemoprevention for high-risk populations. Second, these molecular targets with a clear and well-reasoned link to common exposures may serve as biomarkers for early detection and in the diagnostic or prognostic classification of cancer. Third, untangling the complex interplay between extrinsic/intrinsic exposures and the somatic genome and establishing the sequence of events from exposure to pre-malignancy to cancer may inform strategies for rational anti-tumour therapeutic development. An exhaustive set of tumour molecular changes will be evaluated but a particular focus will be on mutational signatures and anti-tumour immune cell infiltrate signatures, given that these may determine response to chemotherapy, and targeted and immuno-oncology treatments.

The United Kingdom's (UK) population is ageing. As a result, common age-related diseases, such as stroke, fractures and dementia, are predicted to pose an increasing burden on the health system. The development of prevention strategies is therefore an imperative. Emerging evidence has suggested mechanistic links between these age-related diseases. For example, higher risks of hip fractures and dementia have been observed in people who have had a stroke, while a higher risk of hip fractures has also been observed in people who have dementia. These associations may be partly due to the first condition altering the risk of the second condition, but recent evidence suggests that the three conditions might share common risk factors including diet. Of the potentially modifiable risk factors, differences in the amount and quality of dietary protein intake have been suggested to be important. Specifically, low intakes of high quality protein have been associated with higher risks of haemorrhagic stroke (the more aggressive stroke type) and of hip fractures, possibly because protein is a key structural component for maintaining the strength and integrity of blood vessels and bones. The possible relevance of dietary protein intake in the risk for dementia development has been less studied, but low blood levels of insulin-like growth factor I (IGF-I), a peptide hormone that is known to be influenced by dietary protein intake, have been suggested to increase the risk of dementia as well as stroke and fractures. Research is needed to understand the effects of dietary protein adequacy and quality on common age-related diseases. This is particularly relevant in light of the global calls to limit animal source food consumption due to their high environmental impact, though these foods are generally considered higher quality proteins. Understanding the exact role of protein adequacy and quality will guide strategies to ensure optimal protein intakes, without compromising sustainability targets. This research will examine the role of dietary protein intake, focusing on quality as well as quantity, and protein-related biomarkers in the development of stroke subtypes, hip fractures, vascular dementia and Alzheimer's disease, and seek to clarify the links between the three sets of conditions, using data from large prospective cohorts in the UK and in other countries. The first work package will examine how differences in intakes of dietary protein, protein from different sources and protein rich foods affect the risk of each of the conditions of interest. I will also investigate the role of individual dietary amino acids, which make up dietary proteins, with the aim of investigating the association between protein quality and health. The second work package will explore how differences in protein intake influence the levels of protein-related biomarkers in the body, and how these biomarkers may be associated with disease risk, as a way of identifying potential disease mechanisms. This will include the examination of established clinical biomarkers (e.g. IGF-I), circulating amino acids and approximately 1500 novel circulating proteins (proteomics). It will also involve the use of genetic instruments to establish the causal relevance of the biomarkers of interest for disease risk. The third work package will investigate the mechanistic links between the three sets of diseases and the sequence of multimorbidity. I will identify the common dietary and non-dietary risk factors for the three outcomes, and evaluate whether the manifestation of the first condition has a direct effect on the development of multimorbidity, independent of the common risk factors. Overall, this programme of work will generate robust evidence on modifiable risk factors for common age-related diseases and the potential underlying mechanisms, and inform the optimal targets for strategies in disease prevention.

United Nations Sustainable Development Goal 3 (SDG3) sets ambitious targets for improving health and wellbeing globally by 2030. This includes targets for reducing the number of people dying early from cancer, and the number of newborns dying for preventable reasons. It includes targets for dramatically reducing the number of hepatitis B and hepatitis C infections, and for stopping all cases of HIV being passed from a mother to baby. The goal also calls for universal access to sexual and reproductive health care. Many of these areas disproportionately impact on the health and wellbeing of women and make gender inequality worse. This conflicts with the aims of SDG5 which aims to reduce such inequality. If the targets for women in The Gambia and other parts of West Africa are to be achieved, a dramatic increase in progress is essential. A recent review highlighted that one of the main reasons that progress has been too slow so far, is a lack of reliable information on the burden of given health conditions. This was found to be a particular problem in West Africa compared to other parts of the world. The proposed survey will specifically address this and aims to drive improvements in key areas for the health and wellbeing of women in The Gambia and other parts of West Africa as follows: Human papillomavirus (HPV), which is sexually transmitted, causes cervical cancer, one of the most common causes of cancer death in women in Africa. There is already a vaccine against HPV which has been shown to be very good at preventing cancer in women in high income countries. The vaccine is going to be introduced in The Gambia and it is now essential to be able to monitor how good it is in West Africa too. Measuring how much HPV females in The Gambia have before the vaccine is introduced is critical for this and is an important aim of the survey. It may be that there are better, or easier, ways to give HPV vaccines and that improved vaccines become available too. The information from the survey is essential if we are to predict and measure this and ultimately reduce the number of women dying early from cervical cancer in West Africa. Other sexually transmitted infections (STIs), including syphilis, gonorrhoea, and chlamydia, are important causes of preventable deaths in newborns, of stillbirths, of infertility and of other sexual and reproductive health problems. For infections like gonorrhoea, resistance to many antibiotics is increasing too in some parts of the world. We do not know how big a problem this is in West Africa. The survey will measure how common STIs and antibiotic resistance are in females in The Gambia. This information will first, improve the way we treat STIs in The Gambia and other parts of West Africa and second, drive the development of new tests for the infections, and new vaccines to prevent them. Hepatitis B and C are the leading causes of liver cancer in West Africa. Hepatitis B is preventable by vaccination and providing the vaccine to newborns in the first 24 hours of life prevents the infection being transmitted from mother to baby. Medicines that can cure hepatitis C are available. It is also possible to prevent HIV being transmitted from mother to baby. To do this it is essential the mother knows she has the infection during pregnancy and that the baby is given medicines when it is born. The survey will measure how common these three infections are in women of childbearing age. It also aims to identify those factors in the Gambian health system that mean the effective prevention and treatment strategies which exist are either not available or not implemented correctly. In summary, information from the planned survey aims to accelerate progress towards SDG3 in key areas and thus will have much needed positive impact on the health and wellbeing of women in West Africa.