Clinical Genetics

Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted Screening in men at higher genetic risk and controls – The IMPACT study (1002346)

IMPACT is an international study which aims to discover whether screening to detect prostate cancer can be targeted at men who carry the BRCA1, BRCA2 and Lynch Syndrome alterations, leading to an earlier diagnosis and improved survival. It also aims to discover whether men who carry these genetic alterations are more likely to die from the disease, and/or develop an aggressive form of the disease (one that is fast-growing).

A randomised double blind dose non-inferiority trial of aspirin in Lynch syndrome (1506019)

A randomised double blind dose non-inferiority trial of a daily dose of 600mg versus 300mg versus 100mg of enteric coated aspirin as a cancer preventive in carriers of a germline pathological mismatch repair gene defect, Lynch Syndrome. Project 3 in the Cancer Prevention Programme (CaPP3).

Investigating Hereditary Cancer Predisposition – IHCAP (1412029)

Hereditary cancer is an important cause of morbidity and mortality and over the last 20 years, the majority of genes that confer high cancer risk when inherited in a mutated form such as BRCA1, BRCA2 in breast cancer and APC, MLH1, MSH2 in colon cancer have been identified. However there are many men and women who have a strong family history of cancer for whom we cannot provide answers because no mutation is found in known genes.

The objective of this study is to use innovative genomic technologies such as exome sequencing and whole genome sequencing in combination with functional assays to identify new candidate genes in individuals and families with a suspected hereditary cancer.

Phenotypes in Intellectual Disability (1506104)

This project will investigate how different genetic abnormalities can affect brain development leading to ID. In some families, ID is inherited as an X-linked trait, and a specific sequence abnormality has been described consistent with a single gene defect causing disease. In other individuals, an unusual chromosome pattern (translocation) or small missing or extra section of a chromosome (deletion or duplication) is picked up. It is possible to pinpoint the specific gene responsible for ID in an increasing number of individuals.

Splicing and Disease (1606259)

It has recently been recognised that many gene sequence variations found during genetic testing may cause disease by altering gene splicing. Splicing is an essential part of the processing of genes before the protein is made. In particular, changes which had previously been though to be benign may not actually be so. The studies test the hypothesis that some of these gene sequence variants are pathogenic by using either direct RNA analysis or a minigene assay. The result would not otherwise be detectable by other methods and will provide important diagnostic and recurrence risk information for the families concerned. Furthermore this knowledge allows the development of possible future correction strategies which can be tested using patient cell lines.

AD-Genetics (1606261)

Focused on identifying rare genetic variants of moderate to strong effect observed in the coding regions of genes. We will perform a large, powerful study in which we compare 300,000 rare DNA variants from throughout the human genome, in 20,000 AD cases and 49,000 controls. Through sample collection and collaboration we will enrich our clinical samples to include 1000 individuals with early-onset AD. This group are more likely to have rare genetic changes of moderate to large effect on their development of disease.

Genetic mechanisms in polyposis of the bowel (1609304)

Colorectal cancer (CRC) is one of the most common cancers worldwide, with over one million new cases diagnosed each year. There is a considerable strongly heritable component, recognition of which is important for precise diagnosis and patient and family management. High-penetrance germline mutations predisposing to CRC include those affecting the adenomatous polyposis coli (APC) gene, which causes familial adenomatous polyposis (FAP) [1]. FAP affects about 1 in 7000-8000 individuals who are predisposed to hundreds to thousands of adenomatous polyps within the colon and rectum [2]. These polyps are not cancerous but their presence greatly increases the likelihood of the individual developing CRC. A phenotypically ‘less-severe’ form of FAP also exists, termed attenuated-FAP (AFAP). This is characterised by a reduced adenoma burden and a later age of adenoma (and thus cancer) development. 

POD Study (1701357)

Overgrowth disorders are a group of rare genetic conditions that cause children to be larger than others of the same age. They are associated with a wide spectrum of medical problems, including learning disability, congenital abnormalities, and in some cases an increased risk of developing tumours. Overgrowth disorders are genetic, either inherited from a parent or occurring for the first time in a child, and lifelong.

The medical complications, prognosis and recurrence risks for an individual with overgrowth are determined by the underlying cause, and achieving a diagnosis enables optimal care to be provided. In recent years a number of novel genes have been identified, but the clinical course of these conditions is not yet known and access to genetic testing is limited. Even in individuals with a diagnosis of a relatively well known condition, the clinical features can differ from expected, suggesting the existence of genetic modifying factors. There are also many individuals who do not have a clinical or molecular diagnosis, indicating that there are other novel causes of overgrowth yet to be discovered.

This project will study many individuals with overgrowth disorders. Data including history and examination, complications, laboratory investigations, imaging, clinical photography and molecular genetic data will be recorded in detail and held on an access controlled secure public database managed by the NIHR Rare Diseases Translational Research Collaboration.