Academic research community (GECIP)

Akin to the caps on the end of shoelaces telomeres are structures that cap the ends of human chromosomes and protect them from damage. When telomeres stop working the chromosomes can become damaged and this helps tumours evolve to become more aggressive and less responsive to treatment. This project aims to use genomic data from breast and blood cancers to understand the mechanism by which dysfunctional telomeres can lead to genetic changes across the cancer genome. Ultimately this may lead to the development of clinical tools that will aid prognosis and prediction of response to treatment

Acute myeloid leukemia (AML) is a highly aggressive haematological cancer. Although the induction treatment can induce remission in 70-80% of patients, the majority of patients will eventually relapse, and thus cure rates remains low (<40%) even in younger patients (<60 years old), who can tolerate curative intensive chemotherapy. Therefore, there is urgent unmet medical needs in treatment of AML. One major cause of relapse is considered tumor heterogeneity (i.e., a patient has a variety of different AML cells, some of which can survive chemotherapy and subsequently expand.) Tumor heterogeneity was poorly understood because of technical limitations. Conventionally tumor was analyzed in bulk tissue samples, which means that many cells (e.g., 100,000 cells) are pooled together, and we could observe only the average of many cells. Therefore the unique features of each cell could not be observed. Recently single cell technologies have been rapidly emerging, which enable us to observe each cell. Such technologies will reveal the tumor heterogeneity in each patient. We aim to leverage the state-of-the-art single cell technologies to better understand the mechanism of relapse/refractory to identify novel therapies and to provide personalized treatment.

Cancers are caused by changes in DNA (variants) that drive tumour growth. Identifying these variants has produced benefits, such as new targeted treatments. Acute myeloid leukaemia is an aggressive leukaemia (AML) and in adults is associated with a poor 5-year survival (15%). Genetic studies of AML have focused on variants that cause changes in the proteins that genes encode, without considering the 98% of the cell's DNA that does not directly make proteins. We already know of a few variants in this "non-coding DNA" that are important for cancer growth, but there has not been a comprehensive analysis. It is now timely to add non-coding variants to the catalogue of cancer drivers and decipher their functional consequences. We will combine DNA sequencing, other methods to identify new variants in non-coding and other regions of the DNA that are cause AML. This work may lead to new strategies to treat AML.

Acute lymphoblastic leukaemia (ALL) is the commonest childhood cancer, occurring in approximately 400 children each year in the UK. Although many children can be cured, a significant number still die from the disease. Recent work has focused on trying to identify which children have leukaemia that can be cured easily with current chemotherapy and which children have leukaemia which is much harder to treat and will therefore need stronger chemotherapy or new types of treatment. This work has shown that children who fail to respond to the first four weeks of treatment, called ‘primary refractory’ leukaemia, have a very poor outcome. Importantly, primary refractory leukaemia occurs more commonly in a subtype of ALL called T-ALL, occurring in 10% of T-ALL cases. However, at present, we do not know why these children have such aggressive disease and, unfortunately, we do not have any available therapy for many of these patients. Cancer is a genetic disease, which means that it occurs due to changes in the genetic code of the cell, which is contained in the cell’s genes. Whilst It is well known that ALL occurs due to variants in the genes in an immature blood cell, we do not know the exact changes that occur in primary refractory T-ALL. This project therefore aims to perform detailed analyses on leukaemia bone marrow samples collected from patients with primary refractory T-ALL. We will use state of the art sequencing techniques which allow us to read the DNA blueprint of each tumour to identify the genetic changes that cause this type of leukaemia. Further work will look at how these changes affect blood cells and it is hoped that this greater understanding will lead to the development of new treatments to target this disease and improve patients’ outcomes.

This research aims to gain new insights to the genetic basis of a group of cancers of the bone marrow - the myeloproliferative neoplasms (MPN). In a large cohort of MPN patients we will evaluate the genomic structure and variants and correlate this work with clinical data to discover which variants influence the disease, its progress and patients' response to treatment.

Understanding the mechanisms of tumour development is essential to stratify cancer patients for the best available treatment. This process strongly relies on the accuracy of calling somatic and germline (inherited) variants from the paired tumour and normal samples collected from the patient. Unfortunately, normal samples collected from patients with haematological cancers are frequently contaminated with tumour cells and therefore can reduce sensitivity of somatic variant calling. We need a reliable statistical method for estimating tumour in normal (TIN) contamination

Chronic Lymphocytic Leukaemia is one of the most common adult Leukaemia’s in the western world. Current practice at diagnosis can include testing for specific alterations in the DNA of the cancer; variants in the gene TP53 or a large deletion on chromosome 17. Patients who have these alterations will respond differently to treatment compared with patients who do not, allowing clinicians to tailor treatment to the individual. However, there are still many patients who will not respond well to treatment with no identifying marker for why this might be. Here, we harness the powerful method of whole genome sequencing (WGS) to identify new genetic markers in patients with CLL. Further, pre-existing screening for genetic markers requires multiple tests, and we show how WGS can provide comparable results in a single test. Finally, we use WGS to combine multiple risk-factors into a single test to better predict a patient’s disease progression.

Cancers of the same type can be further sub divided based on large scale differences such as gain or loss of part of a chromosome. Smaller genetic changes seen exclusively in tumour cells but not matched normal cells can be grouped by the type of change and by the sequence they arise within. This information, known as the tumour signature can provide insights into the processes involved in the development of tumours. We intend to classify a type of blood cancer, chronic lymphocytic leukemia (CLL) by gains and losses of specific parts of chromosomes. We will then establish the tumour signatures of each class of CLL with the aim of gaining insights into how the cancers developed and how they might be targeted therapeutically. We will compare signatures seen in CLL to those observed in other cancer types.

Acute lymphoblastic leukemia (ALL) is the most common paediatric cancer in Western countries, and accounts for around 100,000 deaths globally each year. This project will analyse DNA of ALL patients in both their normal tissue and the tumour itself to identify variants contributing to the development of the cancer. Through studying these variants, we hope to identify new drug targets, or cases where existing drugs could be used to improve patient outcome.

The MSc in Precision Cancer Medicine has got 8 multidisciplinary modules of 7-8 lectures each. Module 4 is a practical introduction into bio-informatics with a focus on next-generation sequencing analysis.

We are using sequencing information of a maximum of 2-3 chromosomes of a single patient to demonstrate students the principles of whole genome sequencing analysis. As part of this, students are encouraged to access the dedicated MSc folder of the CLL Pilot data and to practice on the data. For the practice exercise that will be marked, students are required to export their analysis on 2-3 chromosomes of a single patient. This analysis contains quality and sequencing metrics.

New students are recruited every year.

Pre-cancer conditions involving B cells occurs in up to 15% of people over the age of 65. The vast majority will not progress to leukemia or myeloma, but are apprehensive and currently require regular follow-up as clinicians cannot tell whether or not they will get cancer. For the small number of patients who progress, they cannot be cured by the time they need treatment. We think that if these small number of people could be reliably identified early before the tumor progresses, we would be able to achieve cure.

Oxford Pre-cancerous Lymphoproliferative Disorders: Analysis and Interception Study (OXPLORED) is a study that aims to identify markers for early prediction of the development of B cell cancer in people at risk. If successful, we will be able to reassure the 95% of people who will never progress, and potentially prevent cancer in the remaining 5% of patients at high risk through early intervention.