Bruce Ponder scientific summary

Previous and current research

The common cancers tend to cluster in families. Most of this family clustering probably has a genetic basis. Knowledge of the genes can be applied in two ways:

• to elucidate normal and abnormal function and thus to understand better the processes of cancer development, and
• to define individuals at risk and to target these individuals for screening and prevention.

Population-based studies by our group and others have shown that BRCA1 and 2 account for only about 20% of inherited susceptibility to breast cancer. Modelling based on patterns of familial clustering of breast cancer in a large population-based set of cases from the Anglian region suggests that much of the familial effect is the result of the combined action of many genetic variants, individually of small effect. We are now using a variety of strategies to search for these variants, to understand how in combination they alter susceptibility to cancer, and how they can be applied to prediction of risk for individuals.

In 2007 we published the first genome-wide search for genetic variants that predispose to breast cancer (Easton et al., Nature 2007; 447:1087). To date, the effects of 5 variants have been confirmed in follow-up studies based on a world-wide collaboration of over 20 research groups; others are in process of confirmation.

We have shown that the variants with the strongest effect, in the gene FGFR2, probably act by altering transcription factor binding and the level of FGFR2 expression (Meyer et al., PLoS Biology 2008; 6:e108). We have also shown that in combination, the 5 variants identified from the genome-wide study and the two others so far identified in other studies, can define a range of individual risks within the population which is of potential utility in the targeting of breast cancer screening (Pharoah et al., NEJM 2008; 358:2796).

Our future research is focussed on:

1. the identification of further susceptibility variants (in collaboration with Doug Easton, Paul Pharoah and Alison Dunning in Cambridge);
2. understanding how the different variants combine to perturb gene expression and cellular phenotyping, and hence susceptibility;
3. developing a framework for variant-based risk prediction and its application in public health.

Our progamme is in a collaboration with the groups of Doug Easton and Paul Pharoah in the Strangeways Research Lab.

Strangeways combines under one roof a unique set of expertise in epidemiology, large-scale population based sample collections, biostatistics, wet-lab genotyping and public health. The research in CRI will complement this by providing resources for functional studies and phenotyping, animal models, and molecular markers for future studies of early diagnosis and prevention.