Mapping tumour molecular mechanisms associated with common exposures: a new approach to identifying targets to prevent and treat cancer

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.

This project has the potential to achieve significant and far-reaching impact in three ways. First, by testing for association between a range of everyday lifestyle exposures or internal factors (such as insulin resistance) and specific somatic molecular mechanisms on the pathway to cancer, it will generate a catalogue of precise molecular targets for further preventative intervention. The availability of a target would mean that such intervention could go beyond policies aimed at ameliorating the harms from the factor (such as behaviour change interventions that are often hard to achieve in practice) and potentially take the form of primary chemoprevention for high-risk populations. Second, these molecular targets with a clear and well-reasoned link to common exposures/risk factors may serve as biomarkers for early detection. They may serve in the improved diagnostic or prognostic classification of cancer informed by an understanding of causal cancer etiology. Third, untangling the complex interplay between extrinsic/intrinsic factors and the tumour genome and establishing the sequence of events from exposure to pre-malignancy to cancer may catalyse the development of anti-tumour therapeutics that are grounded in human germline genetic evidence.

Chemoprevention in those at high risk of developing cancer, biomarkers for earlier diagnosis or better prognostication, and innovation in medicines discovery will, in turn, impact:

(i) The population at risk of developing cancer and patients already diagnosed with cancer:

Over 360,000 people are diagnosed with cancer and nearly 160,000 die as a result of cancer every year in the UK. Prevention remains the cornerstone of reducing the burden of cancer morbidity and mortality. By identifying associations between common exposures or putative risk factors and specific tumour molecular features that drive cancers, this project will inform the development of more precise preventive interventions or policies and help tailor medical advice beyond a one-size-fits-all approach to one that is guided by personalised lifelong genetic trajectories of the underlying risk factors.

(ii) Human capital within the UK economy, and the National Health Service:

The loss to human productivity attributable to cancer in the UK is estimated at about £18 billion each year, while cancer costs the NHS over £5 billion annually. Again, prevention and early detection are imperative to successfully reduce the burden of cancer. In general, cancer detected in its earlier stages is less expensive to treat and has higher likelihood of being cured.

(iii) The UK pharmaceutical and biotechnology industry:

The UK pharmaceutical industry has led the development of poly ADP ribose polymerase (PARP) inhibitors and related companion diagnostics that guide the use of these medicines. PARP inhibitors are a recent class of cancer drugs that are increasingly being used to treat a variety of cancer types and the annual global market for these drugs is estimated to cross £700 million in 2027. The development of PARP inhibitors has emerged from an integrated understanding of the interplay between the germline genome (mutations in the genes BRCA1 and BRCA2 and their effect on cancer risk) and the somatic genome (mechanisms of DNA damage repair acting within tumours). This project aims to use the germline genome to proxy exposures/risk factors and link them to somatic molecular pathways across several major cancer types and therefore has the potential to identify fresh targets for future therapeutic development using the development of PARP inhibitors as an exemplar.