Research Projects

Cancer Genetics

Advances in surgery and chemotherapy have improved the survival of many patients with cancer.  However, for patients with potentially curable cancers, it still remains very difficult to distinguish those at high risk of relapse from those at low risk, and therefore identify those who require chemotherapy in addition to surgery.   Current methods rely on morphological and histopathological assessments, but there is increasing evidence that molecular markers are important in informing prognosis and treatment selection for patients.
This project will employ a range of technology approaches to characterise molecular markers of tumour behaviour and germline variants.  There will be a particular focus on colorectal cancer and melanoma. These platforms include next generation sequencing, array based methods for copy number variation, single nucleotide polymorphism (SNP) typing and pathology techniques. It is anticipated that this work will lead to more widespread molecular profiling of tumours in a clinical practice.

To develop and evaluate a range of molecular markers for cancers and assess their clinical utility and feasibility of using them in a clinical setting. 

PI Prof Ian Tomlinson

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Sudden Cardiac Death Syndromes

Sudden Cardiac death syndromes including hypertrophic and dilated cardiomyopathies and long QT syndrome are young onset conditions exhibiting Mendelian inheritance.  Genetic testing for these in the NHS has recently become available in the UK. This was the result of the Oxford Genetics Knowledge Park programme (a UK Department of Health-funded initiative) which catalysed the translation of expertise from Professor Hugh Watkins' research lab in Oxford to the Oxford NHS Regional Genetics Labs.

The SCD genetic tests are now fully commissioned and Oxford remains the lead centre for providing these in the UK, combining as it does the specialist clinical cardiovascular and genetics expertise with the diagnostic laboratory testing service.

The genes currently tested account for approx 65-70% of cases.  Although additional causative genes are known these are not routinely tested due to the limitations of current technology.  We are exploring whether next generation sequencing could improve the SCD testing currently offered in the NHS so that more families with these conditions can be offered genetic testing and cascade screening.

Principal Investigator:  Prof Hugh Watkins

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Retinal Degeneration

Inherited forms of retinal degeneration affect 1 in 3,500 of the population, and are a significant cause of blindness.  Although many of the genes underlying dominant and recessive forms of retinal disease are known, the genetic testing available is very limited because of the heterogeneous nature of these disorders and the fact that individually they are rare. A molecular diagnosis is, however, extremely important in providing an accurate risk assessment to patients and for reproductive risk counselling.

Recently, advances in gene therapy have resulted in clinical trials for Leber's congenital amaurosis gene therapy being set up, with a further trial for Stargardt's disease gene therapy being considered. These trials, and any subsequent treatment modalities based on them, will necessitate genetic testing being undertaken prior to entry to ensure efficacy. The demand for genetic testing for retinal conditions therefore presents a significant translational research opportunity.

The aim of this project is to explore the clinical utility of next generation sequencing for identifying private familial mutations across a wide range of inherited retinal degenerative disorders (autosomal, dominant and recessive, and X-linked). This project will serve as a model for using next generation sequencing to test other highly heterogeneous Mendelian conditions. 

Principal Investigator:  Dr Susan Downes

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Ataxia

Ataxia is the second neurodegenerative condition being studied in the Oxford BRC Genetics Theme (see also retinal degeneration), a group of inherited disorders in which neuronal dysfunction results in a gross lack of co-ordination of muscle movements. Clinically and genetically, ataxia is extremely heterogeneous, but overall it has a prevalence of ~1 in 5000. It is particularly prevalent in ethnic groups where consanguinuity is common.

The aim of this programme is to develop next generation sequencing as a diagnostic tool encompassing all known ataxia genes to support the NHS clinical genetics service.

This work is sponsored in part by the charity Ataxia UK.

PI Dr Andrea Nemeth 

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Brain Malformations

Development of the human cerebral cortex is a complex process involving cellular proliferation and migration. Spontaneous and inherited mutations that disrupt this process result in cortical malformations which are responsible for various forms of mental retardation, including microcephaly, lissencephaly, and in some instances epilepsy. Abnormalities in the structure of the brain give rise to a range of other conditions including cerebellar hypoplasia and hydrocephalus.

There is limited diagnostic testing available for individuals with brain malformations in the UK. Individually the diseases are rare and genetic tests are often only available in overseas labs so comprehensive testing may take some time. The aim of this programme is to explore whether next generation sequencing can be used to rationalise genetic testing for brain malformations and to explore the role of copy number variation in selected genes. This will increase our understanding of the genetic basis of these heterogeneous Mendelian conditions in addition to providing the basis for novel tests in the NHS.

Additional information for patients and professionals is available at the following website  link: http://www.brainabnormalities.org.uk

PIs  Prof Jonathan Flint, Dr David Keays

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Pathogen Surveillance

Traditional phenotype-based typing has been a powerful aid in the recognition and supervision of outbreaks of infectious disease, but its utility has been limited by difficulties in rapidly generating, and processing data to provide useful near-to-real-time information. Molecular epidemiological studies have also been limited by sampling frames which are poorly representative of the underlying population biology and epidemiology, suffer from inadequate phenotype definitions, or lack control for complex interactions between organism, host and environment.

Next generation sequencing has the potential to revolutionise medical microbiology and infectious diseases research by making very fast large-scale sequencing of large numbers of pathogen and host samples cheap and feasible.  The dramatic enhancement in the speed with which samples can be processed, data analysed and results generated means that real-time pathogen surveillance could become possible.

The aim of this project is to assess whether next generation sequencing technologies can be used to change laboratory practice/clinical management of infectious diseases and focus public health interventions in hospitals and the community.

PI Dr Derrick Crook

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Speech and Language

The term Specific Language Impairment (SLI) describes a language deficit that affects children with otherwise normal levels of development in all other areas. A diagnosis of SLI is made after ruling out the presence of other conditions including autism. Autism is a neurodevelopmental disorder characterised by deficits in reciprocal social interaction and communication, accompanied by repetitive and stereotyped behaviours and interests. Whilst SLI and autism spectrum disorders (ASDs) are generally accepted to be clinically distinct, they share many diagnostic features and are highly heterogeneous.

Although genetic susceptibility to complex disorders has focused largely on single nucleotide polymorphisms, there is increasing evidence that chromosomal imbalances such as deletions and duplications are important in the pathogenesis of many complex disorders, including SLI and autism.

Microarray-based comparative genomic hybridisation (CGH) offers a high resolution methodology for detecting these genomic imbalances.  This technology has already been transferred to the NHS where it is increasingly used as an alternative to conventional karyotyping for conditions such as idiopathic learning disability (ILD) and dysmorphisms.

The aim of this project is to assess the potential for applying CGH technology to SLI in a clinical setting. A pilot study will assess the clinical need for such testing and the potential to identify pathogenic chromosomal rearrangements underlying SLI.  Opportunities to extend this work into autism are also currently being investigated.

PI Dr Sam Knight

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Congenital Heart Disease

Congenital heart disease (CHD), the commonest birth defect, is defined as a gross structural abnormality of the heart or intra-thoracic great vessels that is present at birth and is of functional significance. The incidence of congenital heart disease in live-born infants ranges from 5-10/1000 live births in Europe and the USA. 10% of the ~150,000 people over the age of 16 living with CHD have complex disease requiring lifelong care.

Genomic imbalances represent a major cause of CHD, and can range from large deletions to deletions of single exons.  Identification of an imbalance can affect clinical management and reproductive counselling.

Currently there is limited genetic testing for CHD.  Karyotyping is offered to children if there is clinical suspicion of a chromosomal disorder. More localised cytogenetics tests, such as fluorescent in situ hybridisation (FISH), multiplex ligation probe amplification (MLPA) or multiplex amplifiable probe hybridization (MAPH) are offered if there is a strong reason to suspect an abnormality in a specific single gene or locus. Many patients with non-syndromic congenital heart disease, who are not currently offered testing, have genomic imbalances such as a chromosome 22q11 deletion. Moreover, in neonates presenting with CHD, syndromic features can develop over time and are not easily recognised at presentation. Early knowledge of these genomic imbalances can influence patients' treatment and, for adults, may be important for reproductive risk counselling.

The aim of this project is to evaluate the potential utility of array-based CGH as an alternative to FISH and karyotyping in the genetic diagnosis chromosomal imbalances in patients with complex congenital heart disease. This will be achieved by designing a bespoke CGH array and testing it in a cohort of CHD patients with appropriate controls.

PI Prof Shoumo Bhattacharya

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Chronic Lymphocytic Leukaemia

Leukaemia is a blood cancer that results in abnormal proliferation of blood cells. Leukaemia is characterised by abnormal maturation of cells (in this case blood stem/progenitor cells) with accumulation of dysfunctional cells in the bone marrow and blood. Clinically this results in anaemia, infection and bleeding leading to death. It is classified into acute and chronic forms. B-Chronic Lymphocytic Leukaemia (B-CLL) results from the accumulation of mature B cells and is the most common form of adult leukaemia in the Western world.

Clinically and immunophenotypically, B-CLL is a heterogeneous disease. A variety of cytogenetic and molecular signatures have been identified reflecting both differences in responsiveness to conventional chemotherapy and overall survival. In particular, secondary events such as deletions of 17p, 11q, 13p and trisomy 12 have shown to confer differences in prognosis. This has been appreciated in both national guidelines and international guidelines leading to a revision of clinical practice.  Currently, cytogenetic markers are being validated in Phase III clinical trials to risk-stratify patients to different treatment approaches.

However, conventional cytogenetics may be difficult to perform routinely on CLL samples and these methods can be time-consuming and costly. Array based methods can provide high resolution analysis of genome-wide imbalances and loss of heterozygosity (LOH) information which can inform prognosis and treatment selection for patients.

The primary aim of the project is to validate different commercially-available high resolution array-based platforms for use in the routine cytogenetic assessment of B-CLL samples in comparison with conventional FISH analysis. A secondary objective is to link the results to a biological study on leukaemia stem cells (LSCs) in B-CLL establish a hierarchy of molecular events involved in stem cell development and progression.

PI Dr Anna Schuh

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Pre-Implantation Genetic Screening

Chromosome abnormality is of huge importance for assisted reproductive treatments, such as in vitro fertilization (IVF), as aneuploidy rates in human pre-implantation embryos are extremely high. Approximately 75% of human cleavage stage embryos contain at least one aneuploid cell, with more than half of all embryos composed solely of abnormal cells. Many pre-implantation embryos display varieties of aneuploidy never seen during later stages of pregnancy. It is likely that such embryos fail to implant or spontaneously miscarry during the first few days or weeks of pregnancy.

Some of the aneuploidies observed at the pre-implantation stage result from mitotic errors occurring during the first few cell divisions following fertilisation. However, the majority of abnormalities are derived from meiotic errors occurring during oogeneisis. The well-documented increase in oocyte aneuploidy, seen with advancing maternal age, is the primary cause of increased miscarriage rates in older IVF patients. Increased aneuploidy probably also explains the age-related decline in the proportion of embryos that successfully implant after IVF.

Pre-implantation genetic screening (PGS) exists in several forms, but the most widely practised involves the biopsy and testing of single cell from embryos three days after fertilisation (6-10 cell stage).  It is now widely accepted that PGS reduces the incidence of aneuploid syndromes and miscarriage. Despite the successes of current PGS methods, they remain limited, as they fail to detect approximately 25% of chromosomal errors. Clearly, it would be advantageous to develop methods to detect all forms of chromosome imbalance.

To evaluate whether array CGH can be used to identify genomic imbalances in pre-implantation embryos and therefore be used for PGS.  

This project is being carried out in conjunction with the Oxford BRC Women's Health Theme

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Craniosynostosis

Craniosynostosis, the premature fusion of the cranial sutures, affects about 1 in 2,100 children. The resulting distortion in skull growth can lead to many complications, including raised intracranial pressure and problems with vision, hearing and breathing. Oxford is one of four centres in the UK that are centrally funded by the Department of Health (through the National Commissioning Group) to undertake surgery for craniosynostosis, making it an excellent location for investigation of the contribution of genetic mechanisms to craniosynostosis.

The aim of this proposal is to undertake array -based studies of the Oxford craniosynostosis cohort to estimate the prevalence of clinically significant abnormalities in patients with syndromic craniosynostosis and compare this with patients with non-syndromic (sagittal or metopic) craniosynostosis.

PI Prof Andrew Wilkie

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Website Links

www.oxfordbrc.org

http://www.brainabnormalities.org.uk