Academic research community (GECIP)

Bowel cancer is a common disease that 42,000 people in the UK are diagnosed with annually. Unfortunately, ~16,000 people succumb to the disease each year, making bowel cancer the second most deadly cancer in the UK. Approximately 10% of Bowel cancers have a mutation in the BRAF gene. Half of BRAF-mutated cancers develop a trait called microsatellite instability. This patient subset responds well to modern therapies, such as immunotherapy, and has an elevated survival. Those cancers that do not develop microsatellite instability respond poorly to most therapies, and patients with these cancers have a very poor overall survival. Thus there is an urgent need to identify new therapies to serve this patient population. In this study, we will combine cutting edge analysis methods to the Genomics England colorectal cancer data to identify clinically actionable gene alterations and test therapies that we identify from these analyses using 3D bowel cancer organoid models.

My Personal Therapeutics (MPT) offers the Personal Discovery Process (PDP) technology developed at Mount Sinai Medical Center (NY). PDP is a unique methodology to develop ultra-personalised cancer drug therapies, based on patient’s tumour genomes. The discovery platform is based on that real-world patient tumours are made refractory or resistant to current treatments by variants in multiple genes, including genes not previously associated with cancer. Pentavere is one of Canada’s fastest-growing healthcare technology companies, combining Artificial Intelligence (AI) technologies with clinical expertise to harness the full potential of real-world data at high speed and accuracy. By using AI we aim to dramatically reduce the cost and time to determine the optimum therapy when first-line treatments fail. In this project Pentavere will use its AI engine DARWEN™ to support MPT to analyse complex tumour genomic information, patient characteristics and associated outcomes information from Genomics England lung cancer patient’s database. Once cancer driver genetic events are identified MPT will then create fruit flies (Drosophila) carrying a tumour genetically similar to that of the patient. These fly avatars will be used for high-throughput drug screening. Thus, we will identify drug treatments fully tailored to each patient, with specific tumour genetic constitution

Variants, or changes in the DNA in a person's cells, can lead to cancer. Looking at the DNA of tumours can help us to understand the process by which variants accumulate and eventually drive a cell to become cancerous. We can identify these variants by DNA sequencing of tumour and a normal sample from the same individual. We are trying to find new genes that influence the chance that any given person or groups of people will be prone to developing cancer. We can then look at the cancer variants that arise groups of people carrying that gene compared to people who have cancer but don’t have the genetic variant that we think increases cancer risk. This will help provide essential supporting scientific evidence that any new gene that we find is indeed a cancer gene, but also what the effects are within the tumour itself. This might identify specific weaknesses in the tumour make-up that could be exploited in the future to develop new cancer prevention agents and even anti-cancer cancer chemotherapy drugs.

Mismatch repair deficient (MMRd) colorectal cancer arises as a consequence of faulty DNA repair and accounts for approximately 15% of colorectal cancer cases. In recent years the treatment of these cancers has been revolutionised by a new class of drugs called immune checkpoint inhibitors (ICI), showing impressive results in this tumour type. However, whilst increased tumour mutation burden is a predictor of response to ICIs, the underlying reasons for variation in mutation burden in this tumour group remains unclear. This project will investigate the mechanisms used by these tumours to alter mutation rate and burden.

In the last decades, genomic research has shown that each cancer is different and has a unique repertoire of variants in its genome. Our study aims to use genomics to identify vulnerabilities in cancer cells that could be used as treatment targets. In cancer cells, specific variants lead to faulty genes that do no longer perform their usual function. In this case, cancer cells depend on other genes that can compensate for the lost function. This dependency represents a vulnerability to the cancer cell as the compensating gene can be targeted, and cells may not survive the loss of both genes. In this project, we will use samples from participants in the 100,000 Genomes Project with colorectal cancer. The participants are also part of a separate project with King's Health Partners Biobank through which cancer tissue will be collected. We will use the cancer tissue to establish three-dimensional cultures for each sample in the lab. The genomic data for each cancer will be analysed, and its unique vulnerabilities will be identified. We will then use cutting edge techniques such as gene editing to target these vulnerabilities and study the effect on the cancer cells.

Bowel cancer is the second commonest cause of cancer death in the United Kingdom, with over 16 000 deaths a year. The death rate has fallen significantly in the past 40 years, due to improvements in screening, diagnosis and treatment. Most patients have surgery, with some also requiring chemotherapy and radiotherapy. However, where cancer has spread to other organs, there are very few treatment options and survival is low. The development of a new type of therapy, immunotherapy, which boosts the immune system to help the body destroy cancer cells, has offered a potential avenue of hope. Currently, only a small proportion of patients with bowel cancer are treated with immunotherapy. These patients have genetic markers that show a high immune response to cancer. We will study the differences in how the immune system detects cancer cells, and compare these to genetic changes. We can then identify genetic markers that suggest good responses to immunotherapy, and expand the number of patients who could benefit from this treatment. The 100 000 Genomes Project is collecting genetic information from people with cancer and rare diseases. We will study patients with bowel cancer enrolled in this project and investigate the effects of differences in patient’s immune systems and the genetic changes that occur in tumour cells on the response to bowel cancer. We will also grow tumours in the laboratory and study methods to increase the immune response to cancer treatment. We aim to discover new genetic and tumour markers in bowel cancer that can be targeted by immunotherapy. This will enable us to develop clinical trials of immunotherapy targeting a wider patient group than is currently eligible for this treatment. This will be a major advance in the understanding and treatment of bowel cancer, contributing to the development of personalised treatments of cancer based on specific assessments of genetic markers. It will open a new treatment option to many patients with bowel cancer and help to save lives.

The growth of any cancer is affected by how it interacts with the immune system. Cancer cells have many genetic changes (variants) making them different from healthy cells. Some of these changes are presented on the surface of each cell. The immune system can detect this “foreign” material and attack the cancer. On the other hand, some other variants can help the cancer hide from the immune system despite its genetic changes. Understanding this cancer-immune interplay is crucial for developing better treatment. In this work, we will examine the genetic material of colorectal cancers and look for variants that matter for the immune system. Certain types of colorectal cancers have way more variants than the majority of cancers and therefore they provide an interesting question to explore how the immune interaction is different in these. Do cancers avoid the immune system by in general producing less “foreign” variants? Or do they actively hide by having very particular alterations? Are some cancers more reactive with the immune system because of the inherited immune type of the patient? Using different measures of how strong the tumour-immune interaction is in an individual tumour, we will estimate which patients could potentially benefit from a specific cancer therapy aimed at their immune system.

Although the number of variants that help a cancer to grow varies among cancer types, there is also striking variation among cancers of the same type. Specifically, whilst a typical cancer has about 5 of these “driver” changes – mostly involving small-scale sequence changes in genes like KRAS, TP53 and PIK3CA – a few have no identifiable driver changes and many have just a single change. About 5-10% of colorectal cancers, for example, carry no identifiable driver small-scale variants other than in the APC gene. We wish to explore why cancers such as these can grow, apparently readily, despite their deficiency of driver genes. An obvious reason is that standard sequencing technology and data analysis miss some variants. Alternatively, the “missing” driver genes might be activated or inactivated by “atypical” changes that have the same effect as SNVs or indels, including copy number or structural changes, epivariants or other forms of epigenetic change, SNVs or indels in non-coding regions, et cetera. We aim to determine whether cancers with an apparently low driver mutation burden actually have equivalent functional derangement, using one or more of additional data analysis methods, methylation and gene expression profiling, and long read sequencing (as samples allow). If we do find cancers with a truly very low driver mutation burdens, we shall determine whether their clinicopathological, molecular and evolutionary differ in any way from typical cancers of the same type. The study has potentially important clinical implications for the use of molecularly targeted therapies.

Colorectal cancers very often have large-scale alterations to their genome, such as the loss and gain of whole chromosomes. How these gross variants events occur over time remains uncharacterised. We will apply a new method that uses the pattern of ‘small variants’ (changes to single bases of DNA) to infer the timing and order of ‘large variants’ (loss/gain of large regions of chromsomes). The result will be an improved understanding of how and when colorectal cancers start to develop, and we hope this knowledge will be useful for improving prognostication for cancer patients.

Inflammatory bowel disease is a group of conditions consisting of Ulcerative colitis and Crohn's disease. Patients with this disorder are more prone to developing colorectal cancer. It is currently unclear why some patients develop colorectal cancer and if this type of cancer is different from other types of sporadic colorectal cancer. We propose to analyse the sequencing data from within the 100,000 genome project to compare cases of colorectal cancer arising from patients with IBD and compare them to the general public. We envisage that this will advance our understanding of inflammatory bowel disease related cancers and develop new strategies to identify individuals at risk and potentially identify alternative treatment options.

The proteins isocitrate dehydrogenase (IDH) and ten-eleven translocation (TET) are involved in the development of several types of cancer, including brain tumours (e.g. gliomas) and leukaemias (e.g. acute myeloid leukaemia). It has been suggested but never established over many years of research that the two may functuion as part of the same pathway of driving cancer formation. It has been suggested that a mutation to IDH will in turn prevent TET from performing its normal function in controlling gene expression and stem cell activity. If this occurs, it may be that the lack of TET activity will allow stem cells to accumulate and divide out of control, leading to the formation of either a solid tumour mass or another type of cancer (e.g. leukaemia). In addition to this, a mutation to TET on its own (with IDH still being normal) may also drive the formation of cancer via the same mechanism of stem cell accumulation. Our previous work involving mice has generated some positive data that has allowed us to hypothesise the aforementioned mechanism. Mice that have a mutation to IDH developed glioma through the rapid and uncontrolled division of stem cells n the compartment of the brain where stem cells reside (the "stem cell niche"). In order to confirm our previously mentioned hypothesis that activity of TET is critical in order to prevent cancer development, we require samples from the 100,000 Genome Project of any type of cancer that has a mutation to any variant of IDH or TET. These variants can include: IDH1, IDH2, TET1, TET2 and TET3. We will then be able to perform a series of tests on these samples, comparing the phenotype of IDH and TET-mutant cancers by looking at the activity of stem cells within the samples. If the phenotype is the same in both IDH and TET-mutant cancers, we may be able to prove that our previously hypthesised mechanism of TET-mediated cancer development is accurate. Therefore, by understanding the way in which variants to a gene are able to drive cancer development, we will be able to use this knowledge in the future to develop more effective treatment and diagnosis strategies.

Cancer spread, or metastasis, is a process that involves a cancer cell acquiring new functions to surivive in new tissues. The genetic changes which underpin these changes are not known. Within the cancers in the genomic england project, some are metastatic and some are from the original tumour. We will attempt to understand the changes observed during cancer metastasis and see how they differ from the tumours they arise from. By performing such an analysis, we will have a much greater understanding of this process, but also potentially develop new biomarkers to predict or better treat patients with colorectal cancer.

CRC is becoming more common in those aged under 50. We would like to compare the clinical and genetic features of tumours from cases diagnosed age 70. We will also look for DNA variation in blood samples from the early onset cases to determine whether there were inherited factors that increased risk of colorectal cancer developing.

The study of rare inherited cancer syndromes has shown that, in almost all cases, mutation carriers have an increased risk of several cancer types. This is also true of many of the common, lower risk cancer predisposition genes. We plan to look across multiple types of cancer for new cancer predisposition genes. In most cases, these samples will be derived from the paired normal samples within the cancer part of the 100KGP. These searches will complement our disease-specific work in the colorectal and endometrial cancer GeCIPs and our work in the Inherited Cancer Domain. We expect the most likely class of inherited predisposition gene that we shall identify will be relatively uncommon variation with a moderate effect on cancer risk.

It is becoming increasingly apparent that the development and progression of some cancers are affected by bacteria. This is particularly important for colorectal cancer, which develops under constant exposure to billions of gut bacteria. We aim to study which bacteria are associated with which cancers, and find out if any are likely to cause cancer, or make it harder to treat.

Tumours in colorectal cancer have been shown to display a large amount of heterogeneity, which means that cell types within a single tumour can vary substantially, and that a single tumour is often not a single homogenous unit. It follows from this variation that tumours will evolve in different ways, leading to different severities of cancer, for example, some cell types are able to metastasise to different areas of the body. We will characterise this heterogeneity and order the mutational events using a number of tools, across the large set of colorectal tumours on the Genomics England platform, in order to describe the intricacies of colorectal cancers in unprecedented detail.

While advances in the treatment of colorectal cancer (CRC) have led to improvements in patient outcome, five year survival remains only around 50%. Analysing whole genome sequences of CRC patients will allow us to identify key genes and processes central to development of CRC, and inform on measures to better treat or prevent the cancer.

Using supervised and unsupervised machine learning to specify predictive features of cancer from biological and clinical data.

Between one sixth and one third of bowel and womb cancers carry a much higher than average number of errors in their DNA. We know that in some settings, this is associated with better prognosis and benefit from particular therapies, but the explanations for this are only partially understood. We propose to address this by analysis of the substantial number of these cancers in the Genomics England 100,000 Genomes Project.

While advances in the treatment of colorectal cancer (CRC) have led to improvements in patient outcome, five year survival remains only around 50%. Identifying those at risk of CRC because of genetic predisposition allows for screening and preventative measures to be directed to patients and families at high risk.