Tomlinson group

Research overview

We are chiefly interested in identifying inherited genetic variants that predispose carriers to cancer, and then working out how those variants cause tumours to grow. Our main focus is on colorectal cancer, but we also work on cancers of the uterus, oesophagus, kidney and breast. A large part of our work is based on the study of human patients and their tumours, but we also use cell and mouse models of disease.

Gremlin-1
(Click to enlarge) Schematic of a 40kb genomic duplication upstream of the Gremlin 1 gene that causes the condition hereditary mixed polyposis syndrome and colorectal cancer through disruption of the normal mechanisms that control Gremlin 1 expression.

We have identified six genes that are involved in predisposition to colorectal cancer, two for uterine cancer and two for oesophageal cancer. Three of these genes - Gremlin 1 and DNA polymerases epsilon and delta - harbour high-penetrance mutations that confer a near-100% lifetime risk of developing colorectal tumours. Genetic testing for these variants has been introduced into clinical practice.

We continue our search for genes that carry a predisposition to cancers using the latest technologies allied to careful clinical studies. For selected genes, we are undertaking functional studies in human cells and mouse models to examine the consequences of the inherited variants.

Our other major longstanding interest is cancer as an evolutionary process, especially the relative roles of mutation and selection. In-depth analysis of cancer genomes allows the history of that tumour to be reconstructed, especially if multiple samples from the tumour are analysed. We are particularly interested in the evolution of colorectal tumours, including benign polyps, diversity within primary carcinomas, and disseminated disease.

We are keenly involved in helping to translate the results of our own work and molecular genetics in general into the clinical setting. This is principally achieved through the Oxford NIHR Biomedical Research Centre. Our research roles here include the identification of new molecular markers of prognosis and of adverse reaction to widely-used  chemotherapies, together with the improvement of the molecular classification of cancer. These are coupled to the development of DNA sequencing technologies for implementation in the clinical molecular pathology laboratory.

Funding sources

Cancer Research UK

Oxford Biomedical Research Centre

EU 7th Framework Programme

Wellcome Trust