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

Lead Research Organisation: University of Bristol
Department Name: Bristol Medical School

Abstract

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.

Planned Impact

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.

Publications

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Gabriel AAG (2022) Genetic Analysis of Lung Cancer and the Germline Impact on Somatic Mutation Burden. in Journal of the National Cancer Institute

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Gregga I (2023) Predicted Proteome Association Studies of Breast, Prostate, Ovarian, and Endometrial Cancers Implicate Plasma Protein Regulation in Cancer Susceptibility. in Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

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Larsson S (2022) Serum Estradiol and 20 Site-Specific Cancers in Women: Mendelian Randomization Study in The Journal of Clinical Endocrinology & Metabolism

 
Description The four key objectives of this award were the identification of tumour (cancer) molecular features associated with common exposures or cancer risk factors, the investigation of these tumour molecular features in the context of cancer progression and medicines development, the identification of inherited genetic determinants of tumour mutations, and the investigation of these mutations in the context of cancer risk. We already have considerable evidence to demonstrate that these objectives have been met or are in the process of being met. Through research supported by this award we have already established that several modifiable (e.g., smoking, adiposity) and non-modifiable (e.g., white blood cell telomere length) exposures and cancer risk factors cause specific genetic mutations in blood that lead to common and frequently lethal forms of blood cancer such as acute myeloid leukaemia; we have identified 10 new inherited genetic determinants of key cancer gene mutations in blood, and we have provided detailed estimates of the exact risks of a range of cancer and non-cancer health outcomes associated with these mutations in the UK population. We have also shown that genetic predisposition to higher body mass index is associated with specific changes in gene expression and immune system and mutational signatures in endometrial tumours and that these changes are potentially targetable via drug treatment in endometrial cancer. Finally, our work has also revealed genomic links between the benign precursor condition endometriosis and subsequent ovarian cancer that may be tapped for cancer preventative drug development.
Exploitation Route We have identified multiple new inherited genetic determinants of gene mutations in blood that drive the subsequent development of cancer. We have also identified functional genomic links between adiposity and endometrial tumour biology and between endometriosis and ovarian cancer development. These determinants and links are providing new insights into mechanisms that underlie the acquisition of key genetic aberrations that occur over the course of life and cause cancer. Targeting these mechanisms has the potential to inform the development of new cancer medicines by the pharmaceutical industry.
Sectors Healthcare

Pharmaceuticals and Medical Biotechnology

 
Description Our findings have impacted on the following areas: 1. Our seminal paper in Nature Genetics volume 54, pages 1155-1166 (2022) in particular is informing the approach to management of patients at the recently founded "Clonal Haematopoiesis" clinic at Cambridge University Hospitals NHS Foundation Trust. This is a specialised clinic that reviews local patients referred upon the chance identification of blood somatic cancer driver mutations (clonal haematopoiesis) with a view to preventing myeloid leukaemias and other diseases in these patients. Our identification of multiple new inherited genetic risk factors, and other modifiable (e.g., smoking, adiposity) and non-modifiable (e.g., white blood cell telomere length) risk factors for clonal haematopoiesis, and our estimation of the risks of a range of cancer (such as myeloproliferative neoplasms and solid tumours) and non-cancer (such as atrial fibrillation and epigenetic aging) consequences of clonal haematopoiesis is helping counsel patients attending this clnic. Our results are also now included in online materials prepared by the Genomics Education Programme of Health Education England. 2. Our paper (Nature Genetics volume 54, pages 1155-1166 (2022)) involved a close collaboration with AstraZeneca's Centre for Genomics Research and has been highlighted by AstraZeneca as an exemplar project that is expanding knowledge of the molecular drivers underlying clonal haematopoiesis with the potential to identify individuals predisposed to chronic diseases such as cancer, advancing understanding of how mechanisms can manifest into disease, and helping develop precision medicine strategies that may play a role in preventing the adverse effects of blood somatic cancer driver mutations on human health.
First Year Of Impact 2022
Sector Healthcare,Pharmaceuticals and Medical Biotechnology
 
Description Publication on clonal haematopoiesis formed the basis of Health Education England Genomics Education Programme article on this condition
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
URL https://www.genomicseducation.hee.nhs.uk/blog/under-the-radar-exploring-clonal-haematopoiesis/
 
Title Clonal hematopoiesis GWAS summary statistics 
Description Datasets linked to the pre-print titled, "Genome-wide analyses of 200,453 individuals yields new insights into the causes and consequences of clonal hematopoiesis", which is available at https://doi.org/10.1101/2022.01.06.22268846 To estimate odds ratios from BOLT-LMM betas and standard errors please use the formula provided here. The formula requires the number of controls (= 173,918 for each of the five GWAS) and the numbers of cases (10,203 overall-CH, 5,185 DNMT3A-CH, 2,042 TET2-CH, 4,049 large-CH, and 6,154 small-CH). 
Type Of Material Database/Collection of data 
Year Produced 2022 
Provided To Others? Yes  
Impact This research dataset contains genome-wide summary genetic association statistics for association between inherited genetic variants and clonal haematopoiesis, a common somatic mutational phenomenon in blood. The development of this research dataset has, within our group, lead to new insights into the causes and health-related consequences (such as atrial fibrillation, epigenetic ageing, haematological and non-haematological cancers, etc.) of clonal haematopoiesis. We have made this dataset publicly available and it is hoped that by doing so, the scientific community will be able to leverage the dataset and take our understanding of clonal haematopoiesis even further. 
URL https://zenodo.org/record/5893861
 
Description Collaboration with Tata Memorial Centre/Advanced Centre for Treatment Research & Education in Cancer/Centre for Cancer Epidemiology 
Organisation Tata Memorial Hospital
Country India 
Sector Hospitals 
PI Contribution We are contributing our analytic expertise in performing germline and somatic cancer-focused genome-wide association analyses.
Collaborator Contribution Prof. Rajesh Dikshit and his research group at the Tata Memorial Centre - Advanced Centre for Treatment Research & Education in Cancer - Centre for Cancer Epidemiology in Mumbai, India have performed a germline genome-wide association study of buccal mucosa cancer risk involving a case-control cohort of ~4,000 individuals and exome sequenced the tumours/somatic genomes of ~100 individuals and through this collaboration we are in the process of analysing these data and writing up the results together.
Impact Helped organise a workshop on genome-wide association studies and precision cancer prevention at the Tata Memorial Centre 21st Annual Conference on Evidence Based Management of Cancers in India
Start Year 2022
 
Description Helped organise a workshop on genome-wide association studies and precision cancer prevention at the Tata Memorial Centre 21st Annual Conference on Evidence Based Management of Cancers in India 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Organised a workshop on genome-wide association studies and their role in precision cancer prevention at the Tata Memorial Centre 21st Annual Conference on Evidence Based Management of Cancers in India. Workshop was in person and also broadcast online across India via the country's National Cancer Grid (~130 participants in the workshop, largely cancer-focused clinician scientists but also non-clinical scientists and medical and non-medical trainees in oncology/oncology research). Also delivered a talk on germline-somatic associations in cancer and hosted a panel discussion, all of which generated substantial interest and requests for further research collaboration in the broad area of the UKRI Future Leaders Fellowship.
Year(s) Of Engagement Activity 2023
URL https://tmc.gov.in/index.php/en/ebmhome
 
Description Interview for TV news 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Interviewed as an epidemiologist on NDTV, India's oldest national English language 24x7 news channel to provide expert scientific comments on Covid-19 vaccination, especially booster doses.
Year(s) Of Engagement Activity 2021
URL https://www.ndtv.com/video/news/news/covid-vaccine-government-sources-indicate-no-mix-and-match-of-v...
 
Description Interview for newspaper 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Interviewed by The Hindu Business Line, the business newspaper of The Hindu, the second most circulated English-language newspaper in India and a newspaper of record there. Quoted as a UKRI Future Leaders Fellow and interviewed for my expert scientific comments on the future directions of the Covid-19 pandemic.
Year(s) Of Engagement Activity 2022
URL https://www.thehindubusinessline.com/specials/pulse/preparing-to-live-with-covid-while-strengthening...
 
Description Sanger Institute COSMIC programme blog post and podcast on clonal haematopoiesis 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The Wellcome Sanger Institute's Catalogue of Somatic Mutations in Cancer (COSMIC) programme ran a blog post and accompanying Spotify podcast featuring me and our published work on clonal haematopoiesis (specifically the 2022 Nature Genetics publication "Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis", which I led and which was supported by my UKRI Future Leaders Fellowship (MR/T043202/1)). In the blog and podcast I gave an interview explaining the definition, causes and consequences of clonal haematopoiesis, and explaining our research and findings in this area, in simple terms.
Year(s) Of Engagement Activity 2022
URL https://cosmic-blog.sanger.ac.uk/subtraction-analysis-cosmics-role-in-defining-causes-and-consequenc...
 
Description School Visit (Bristol) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Dr. Victoria Gray, a postdoctoral senior research associate at the University of Bristol, who is funded on my UKRI Future Leaders Fellowship, participated in a visit to a school in an area of low educational attainment as part of a small team of volunteers from from the MRC Integrative Epidemiology Unit, University of Bristol. Classes within the school are interested in specific careers and we were invited to talk about our role as geneticists. We expanded this to introduce children (from years 2-6) on the diversity of scientists, including looks, studies and background and encouraging them to think of themselves as scientists - both now and as a future career path.

In smaller groups, we performed an epidemiology-style experiment to find patterns within the school based on genetic and environmental factors. This involved students separating themselves into groups based on characteristics including birth month, hair colour and personal food tastes. During this we encouraged students to be involved in the generation of theories, observation and data collection.

A plenary activity consisted of showing a slideshow of photos from real scientists all around the world (sourced from Twitter) to show 'what a scientist looks like' and the variety of people who can be scientists. Students were then encouraged to imagine and draw themselves as a scientist for an in-school display. The activity sparked questions and discussions on genetics and epidemiology from the school students and there was increased interest in these areas of science among the students.
Year(s) Of Engagement Activity 2022
 
Description Served as faculty on the European Hematology Association (EHA)-European Molecular Biology Laboratory (EMBL)/European Bioinformatics Institute (EBI) Computational Biology Training programme in Hematology 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Served as faculty member on the Computational Biology Training in Hematology (CBTH), which provides early-career researchers aiming to specialise in computational and quantitative biology aspects of haematology with a unique, year-long training and mentoring experience by top-tier faculty. CBTH is a joint effort of the European Hematology Association (EHA) and the European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI) that aims to support the development of quantitative skills for haematology researchers by organising a training and mentoring program in computational biology. The CBTH program is organised with two multi-day workshops in Hinton, UK and graduation of scholars at the EHA Congress in Frankfurt, Germany. The invitation to serve as faculty on this course was a direct result of our published work on clonal haematopoiesis and germline-somatic interaction in blood cancers.
Year(s) Of Engagement Activity 2023
URL https://ehaweb.org/research/training-and-mentoring/eha-emblebi-computational-biology-training-in-hem...
 
Description Talk at the Intercepting Blood Cancers 2023 meeting in Madrid, Spain 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The first ever Intercepting Blood Cancers (IBC) 2023 meeting in Madrid, Spain provided a unique, interactive platform for presentations on key clinical trial data and expert clinical insights for early interventions in blood cancers and how this impacts outcomes for patients by leading international clinicians and scientists work in this area. One of the key topic tracks was on clonal haematopoiesis and I presented my team's research results on this track, describing current knowledge of germline determinants of blood cancer precursors and how these might enable early clinical intervention. I contributed to a plan for publication and dissemination of consensus findings from discussions arising at the meeting.
Year(s) Of Engagement Activity 2023
URL https://ibc2023.org/agenda/#chip