The Institute of Cancer Research

Molecular and Population Genetics Research

Molecular and Population Genetics Team

Section: Section of Cancer Genetics

 

Non-medullary Thyroid Cancer

Investigators: RS Houlston; in collaboration with W Foukes, McGill University, Canada

 

Non-medullary thyroid cancer (NMTC) accounts for 90% of all malignancies at this site. Six per cent are familial, characterised by a high incidence of bilateral disease and poor prognosis. One large family has been used to identify a familial non-toxic multi-nodular thyroid goitre gene mapping to chromosome 14q (MNG1). Linkage and mutation studies of MNG1, TCO1, PTEN and TSHR using 13 additional multiple case families suggest the disease is highly heterogeneous

External Funding: Cancer Research UK

Inherited predisposition to B-cell lymphoproliferative disorders

Investigators: RS Houlston, G Sellick, Richard Coleman; in collaboration with D Catovsky, E Matutes, Academic Department of Haematology and Cytogenetics; N Caparosa, Section of Genetic Epidemiology, National Institutes of Health; J Wiley, Section of Haematology, Syndey University; A Rawstrom, P Hillmen, UMDS, Leeds.

 

It is now established that a subset of B-cell lymphoproliferative disorders – LPDs-  (chronic lymphocytic leukaemia, non-Hodgkin’s lymphoma and Hodgkin’s lymphoma) are familial. We established an international consortium to collect multiple case families to identify B-cell LPD. Blood samples and clinico-pathological data have been collected from over 300 families and 1,000 unselected cases. Using this resource we are adopting complementary strategies to identify predisposition alleles.

External Funding: LRF

Establishment of a Royal Marsden–Institute Family History and DNA Resource

Investigators: RS Houlston, C Alfleck, S Murphy, L Hughes, E Strong; in collaboration with sections within the Royal Marsden

 

Collection of family history data and blood samples constitutes the basic groundwork of genetic studies of cancer. The Royal Marsden is one of the largest cancer centres in the UK and so offers a unique opportunity to assemble a large bank of DNA from patients with cancer. As a collaborative venture between The Institute and the Royal Marsden a DNA and family history register of Royal Marsden patients has been established and will be used to examine the genetic epidemiology of a wide range of cancers.

This project is funded externally.

Genetic Studies of Proteus Syndrome

Investigators: RS Houlston, K Barker; in collaboration with J Harper, F Mansell, Great Ormond Street Hospital

 

Proteus syndrome comprises an association of asymmetrical gigantism, venous epidermal naevi, vascular malformations, hamartomas and hyperosteosis. These manifestations are invariably present from birth, and an increased risk of malignancy associated with regions of overgrowth has been reported. Using a combination of candidate gene analyses and expression studies are in the process of identifying genes involved in growing normal tissue control.

External Funding: Proteus Society Network

Genetic Studies of Breast Cancer Susceptibility

Investigators: RS Houlston in collaboration with Gill Ross, Section of Radiotherapy; R Aherne, Section of Computing

 

In addition to rare high penetrance susceptibility alleles for breast cancer there is evidence that a proportion of cases can be ascribed to low penetrance alleles. Such alleles are detectable through genetic association comparing the frequency of specific genotypes in cases and controls. It is probable that such alleles interact with lifestyle and environmental risk factors. A large case-control study is being assembled to address this issue.

External Funding: Warburg Fund

Peutz–Jeghers Syndrome

Investigators: RS Houlston, W Lim, N Hearle

 

About 50% of Peutz–Jeghers syndrome is caused by germline mutations in STK11. We have assembled data on over 200 mutation carriers and are assessing the relationship between genotype and phenotype. In addition we are searching for a novel Peutz–Jeghers susceptibility gene through a combination of linkage and physical methods.

External Funding: Cancer Research UK

Multiple Leiomyomatosis

Investigators: RS Houlston, K Barker, B Shah; in collaboration with A Ashworth, Breakthrough Centre

 

The dominant transmission of uterine and cutaneous leiomyomata and renal tumours is seen in familial cutaneous leiomyomatosis. Through positional cloning we identified fumarate hydratase as the gene responsible. We are using RNAi and developing a model system to determine how dysfunction in this component of the Krebs cycle leads to tumour formation.

External Funding: Wellcome Trust, Cancer Research UK

Genetic Analysis of Variable Expression of Neurofibromatosis Type 1

Investigators: RS Houlston, A Norton; in collaboration with K Pritchard-Jones, Section of Paediatric Oncology

 

Neurofibromatosis (NF) type 1 is a dominant disorder with protean features that include an increased risk of malignancy. In addition to inter-familial variability in disease expression, intra-familial differences strongly implicate the action of modifier genes. We have been examining the relationship between genotype and phenotype and have started genotyping families to identify sequence changes in candidate genes that modify disease expression.

External Funding: Cancer Research UK

Genetic Studies of Lung Cancer Susceptibility

Investigators: RS Houlston, E Webb, A Matakidou; in collaboration with T Eisen, Section of Medicine

 

Lung cancer is frequently cited as a tumour caused by exposure to environmental carcinogens. Clearly, smoking is the major determinant of risk, however there is evidence to suggest that part of an individual’s susceptibility may be mediated through inherited genetic factors. Epidemiological data suggest that such genetic factors are likely to be sequence variants conferring modest genotypic risks. Using samples collected though the GELCAPS consortium we are conducting association studies to identify low penetrance susceptibility alleles for lung cancer.

External Funding

Colorectal Cancer Genotypes as Prognostic Markers

Investigators: RS Houlston, S Popat; in collaboration with C Zheng-Ming, Clinical Trials Unit, Oxford

 

Normal and tumour tissues have been obtained from a random subset of 1,000 patients entered into a trial of 10,000 colorectal cancer patients evaluating use of 5-fluorouracil (5-FU). Using this resource we have constructed tissue microrrays and are exploring whether or not tumour genotypes can predict prognosis or response to therapy.

External Funding: Cancer Research UK, AICR

Genetic Studies of Colorectal Cancer Susceptibility

Investigators: RS Houlston, M Rudd, G Sellick, W Wood, C Fleishmann; in collaboration with J Peto, Section of Epidemiology; IPM Tomlinson, Cancer Research UK

 

Using a large systematic series of early-onset colorectal cancer cases we have partitioned familial risks on the basis of mismatch repair phenotype. The estimates of risk we have determined indicate that the major colorectal cancer predisposition genes identified to date do not account for all of the familial risk associated with early-onset disease. This information has implications for counselling and screening. Furthermore, the findings indicate that there is an opportunity to identify additional colorectal cancer genes and have provided a rationale for setting up the CORGI (Colorectal tumour Gene Identification) study. CORGI aims to ascertain and collect families with multiple cases of colorectal neoplasia in order to identify novel predisposition genes through linkage and association using familial cases.

External Funding: Cancer Research UK