Richard Houlston - Overview

The major area of our research is the study of inherited susceptibility to cancer, specifically, the genetic epidemiology of susceptibility genes, and the identification and characterisation of novel susceptibility loci.

To date, our research in genetic epidemiology has focused on colorectal cancer. 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. 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.

The other principal area of our research is centred on the localisation and identification of genes implicated in predisposition to juvenile polyposis, multiple leiomyomata, non-medullary thyroid cancer and chronic lymphocytic leukaemia.

Juvenile polyposis is an autosomal dominant susceptibility to hamartomatous polyps, usually within the colon, but occasionally arising in the stomach and small bowel. Unlike solitary juvenile polyps, which affect ~2% of children and adolescents and have little or no malignant potential, juvenile polyposis is associated with a markedly increased risk of gastrointestinal malignancy. We have shown that germline mutation in SMAD4 and BMPR1A cause of juvenile polyposis.

Dominant transmission of uterine myomata is seen in familial cutaneous leiomyomatosis - characterised by multiple, small smooth muscle tumours in skin and early-onset uterine leiomyomata. Using families segregating this disease we have shown that multiple cutaneous leiomyomata is linked to chromosome 1q42.3-q43 and are in the process of identifying the gene. Using tumours from affected individuals in families with multiple cutaneous leiomyomata we have shown that there is a high rate of allele loss in the vicinity of the susceptibility locus. In linked families the allele lost was always the one inherited from the normal parent. This pattern is precisely that predicted of a gene that is inactivated by mutation of both alleles (tumour suppressor gene, recessive oncogene) and is similar to that observed in many other cancer susceptibility genes.