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.

We propose a new phase of the successful Mathematics for Real-World Systems (MathSys) Centre for Doctoral Training that will address the call priority area "Mathematical and Computational Modelling". Advanced quantitative skills and applied mathematical modelling are critical to address the contemporary challenges arising from biomedicine and health sectors, modern industry and the digital economy. The UK Commission for Employment and Skills as well as Tech City UK have identified that a skills shortage in this domain is one of the key challenges facing the UK technology sector: there is a severe lack of trained researchers with the technical skills and, importantly, the ability to translate these skills into effective solutions in collaboration with end-users. Our proposal addresses this need with a cross-disciplinary, cohort-based training programme that will equip the next generation of researchers with cutting-edge methodological toolkits and the experience of external end-user engagement to address a broad variety of real-world problems in fields ranging from mathematical biology to the high-tech sector. Our MSc training (and continued PhD development) will deliver a core of mathematical techniques relevant to all applied modelling, but will also focus on two cross-cutting methodological themes which we consider key to complex multi-scale systems prediction: modelling across spatial and temporal scales; and hybrid modelling integrating complex data and mechanistic models. These themes pervade many areas of active research and will shape mathematical and computational modelling for the coming decades. A core element of the CDT will be productive and impactful engagement with end-users throughout the teaching and research phases. This has been a distinguishing feature of the MathSys CDT and is further expanded in our new proposal. MSc Research Study Groups provide an ideal opportunity for MSc students to experience working in a collaborative environment and for our end-users to become actively involved. All PhD projects are expected to be co-supervised by an external partner, bringing knowledge, data and experience to the modelling of real-world problems; students will normally be expected to spend 2-4 weeks (or longer) with these end-users to better understand the case-specific challenges and motivate their research. The potential renewal of the MathSys CDT has provided us with the opportunity to expand our portfolio of external partners focusing on research challenges in four application areas: Quantitative biomedical research, (A2) Mathematical epidemiology, (A3) Socio-technical systems and (A4) Advanced modelling and optimization of industrial processes. We will retain the one-year MSc followed by three-year PhD format that has been successfully refined through staff experience and student feedback over more than a decade of previous Warwick doctoral training centres. However, both the training and research components of the programme will be thoroughly updated to reflect the evolving technical landscape of applied research and the changing priorities of end-users. At the same time, we have retained the flexibility that allows co-creation of activities with our end-users and allows us to respond to changes in the national and international research environments on an ongoing yearly basis. Students will share a dedicated space, with a lecture theatre and common area based in one of the UK's leading mathematical departments. The space is physically connected to the new Mathematical Sciences building, at the interface of Mathematics, Statistics and Computer Science, and provides a unique location for our interdisciplinary activities.

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.

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.

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.