We undertake research into inherited tumour syndromes with a particular interest in intestinal polyposis syndromes.

Our team is based within the Division of Cancer and Genetics of the School of Medicine and are made up of specialised groups working in collaboration with the NHS, international colleagues and fellow academics across the University.

Aims

• Characterise the inherited and somatic genetic variation associated with intestinal polyposis syndrome and the tumours that these patients develop.
• Elucidate the molecular and cellular mechanisms involved.
• Use this knowledge to facilitate better or novel approaches to diagnosis, treatment and prevention.

Projects

Current open research studies that are supported include:

1. Genetic mechanisms in polyposis of the bowel - Chief Investigator Dr Hannah West

This study is recruiting across the UK and aims to discover novel genetic mechanisms underlying polyposis of the bowel and the development of tumours in this group of disorders. 12/WA/0071. IRAS 87399

This study has underpinned the identification of a genetic change that reduces the activity of a known tumour suppressor gene, causing the polyposis phenotype seen in a 4-generation family. This genetic change was not identified from the standard clinical diagnostic services because it does not occur in the main body of the gene.

However, this highlights the potential usefulness of expanding the diagnostic screen, particularly for patients with suspected polyposis when a classical genetic change has not been identified.

Short E, Thomas LE, Davies A, Bolton A, Maynard J, Giles P, Mort M, Consoli C, Egner I, Jundi H, Sampson JR. APC Transcription Studies and Molecular Diagnosis of Familial Adenomatous Polyposis. European Journal of Human Genetics. 2020 Jan;28(1):118-121 (IF 3.650) https://doi.org/10.1038/s41431-019-0486-2

Short E, Thomas LE, Hurley J, Jose S, Sampson JR. Inherited Predisposition to Colorectal Cancer: Towards a More Complete Picture. J Med Genet. 2015 Dec;52(12):791-6 (IF 5.899)

DOI: 10.1136/jmedgenet-2015-103298

2. Molecular genetic analysis of duodenal polyposis in the inherited colorectal adenoma and cancer predisposition syndromes (Familial Adenomatous Polyposis and MUTYH-Associated Polyposis) - Chief Investigator Dr Laura Thomas

Patients with familial adenomatous polyposis (FAP) and MUTYH associated polyposis (MAP) are also at risk of developing premalignant and malignant tumours in the duodenum as well as the colorectum.

This study investigates the genetic factors, inherited and somatic, associated with growth and progression of duodenal adenomas to cancer in MAP and FAP. 15/WA/0075 IRAS 158519

Thomas LE, Hurley JJ, Meuser E, Jose S, Ashelford KE, Mort M, Idziaszczyk S, Maynard J, Brito HL, Harry M, Walters A, Raja M, Walton SJ, Dolwani S, Williams GT, Morgan M, Moorghen M, Clark SK, Sampson JR. Burden and profile of somatic mutation in duodenal adenomas from patients with familial adenomatous- and MUTYH-associated polyposis. Clinical Cancer Research. 2017 Nov 1;23(21):6721-6732 (IF 8.911)

DOI: 10.1158/1078-0432.CCR-17-1269

3. Exploring genetic causes of duodenal polyposis using healthy volunteers - Chief Investigator Dr Laura Thomas

This study uses 3D organoid models to explore the genetic causes of duodenal polyposis by comparing affected patients with healthy volunteers.

A comparison of healthy volunteers with 3D duodenal organoids established from patients with FAP and MAP (established as part of 15WA0075) can help to determine how polyps are arising in patients with these conditions. 19/YH/0310. IRAS 268541

4. A prospective Europe-wide study of duodenal disease in MUTYH - Associated Adenomatous Polyposis (MAP) - Chief Investigator Prof Julian Sampson

This first multi-centre European prospective study of duodenal disease in MAP aims to provide evidence as to whether surveillance recommendations developed for patients with FAP are also appropriate for patients with MAP.

It aims to collect long-term data on the endoscopic findings and provide follow-up information to aid understanding of the natural history of duodenal disease in MAP, taking into account that some patients may require therapeutic procedures including removal of polyps where there is advanced duodenal disease. It will also prospectively collect data on the occurrence of colorectal cancer and extra-intestinal cancers. 11/WA/0208 IRAS 13304

Hurley JJ, Thomas LE, Walton SJ, Thomas-Gibson S, Haycock A, Suzuki N, Mort M, Williams G, Morgan M, Clark SK, Sampson JR, Dolwani S. The Impact of Chromoendoscopy for Surveillance of the Duodenum in Patients with MAP and FAP. Gastrointestinal Endoscopy. 2018 Oct;88(4):665-673 (IF 7.229)

5. Genes and the kidney in Tuberous Sclerosis (TSC) - Chief Investigator Prof Julian Sampson

There is a small subgroup of patients with tuberous sclerosis who have severe renal cystic disease resembling that found in adult onset polycystic kidney disease but often with early or congenital onset. We reported contiguous gene deletions involving both TSC2 and PKD1 in these patients in 1994, but little is known about the natural history of the TSC2/PKD1 contiguous gene deletion syndrome into adulthood.

The aim of this study is to determine the natural history of renal disease in patients with the TSC2/PKD1 contiguous gene deletion and compare this with patients with mutations in TSC2 or TSC1 alone. 10/MRE09/3. IRAS 10073

If you would like to know more about these studies, or find out more about how the Wales Gene Park Research Co-ordinator could assist your research, please get in touch with Karen Reed, Reedkr@cardiff.ac.uk

Previous research studies

1. Exome/genome sequencing of TSC no mutation identified (NMI) patients

Mutations in TSC1/TSC2 are known to underlie at least 80% of TSC cases. However, in up to 20% of the remaining cases, alterations in these genes remain are currently unidentified. These “no mutation identified” patients (NMI) may have undetected mutations in gene regions which are not usually screened diagnostically (e.g. promoters or untranslated regions [UTRs]) while some patients with TSC-like phenotypes may have causative mutations in other genes. The aim of this study is to determine the underlying molecular mechanisms for the TSC and TSC-like signs and symptoms in these patients, improving genetic diagnosis for this group of patients. 11/WA/0276. UKCRN ID, 13635

2. Molecular genetic and endoscopic studies of duodenal polyposis in the inherited colorectal adenoma and cancer predisposition syndromes (Familial Adenomatous Polyposis and MUTYH-Associated Polyposis)

The overall aim of this research was to gain a better understanding of the genetic factors that affect the growth of duodenal adenomas in patients with MAP and FAP, and to discover more about how duodenal polyps progress. It also aimed to determine if dye-spraying the duodenum leads to greater detection of polyps, and a better estimation of their size and structure. 10/MRE09/4

Please contact our Research Co-ordinator/ Information Governance Lead Laura Butlin for further information about the studies including patient information sheets and GDPR transparency statements.

Funders

We are grateful to the following funders for supporting our work:

• Wales Cancer Research Centre
• Health and Care Research Wales
• Bowel Cancer West
• Pathological Society of Great Britain and Ireland
• Sêr Cymru
• Wales Gene Park