“The big goal for the next 10 years is to elucidate the 'genetic architecture' of the common cancers.”

The search for the highly penetrant predisposing genes BRCA1 and 2, and subsequently for common low penetrance variants, has been a very active field of research over the last 10 years. My group, together with collaborators, was particularly well-placed to contribute because we combined each of the elements necessary for such work—epidemiology, with large well-described patient populations; molecular genetics for genotyping; statistics; and a clinical base, which is important when seeking to involve large numbers of patients and families in genetic research.

I was led into the genetics of cancer by seeing patients with familial thyroid cancer when I was practicing as an oncologist in 1980. I was aware of the beginnings of genetic linkage using DNA polymorphisms, and I realized that the study of familial cancers would be one way to identify predisposing genes, and thus bring insights into how cancers develop. My initial work was with thyroid cancer in MEN2, but subsequently I extended that to breast and ovarian cancer.

The identification of strongly predisposing genes such as BRCA1 and BRCA2, to which my group contributed, has provided insights into cancer cell biology. We constructed a transgenic mouse with a hypomorphic BRCA2 allele, which was the starting point for the work of Venkitaraman’s group in elucidating many features of the BRCA2 function. In the clinic, after initial anxieties about the effects of giving a genetic diagnosis, it has turned out that BRCA1/2 genetic testing has greatly assisted the clinical management of the families in which these mutations can be identified. The majority of genetic predisposition to cancer, however, is the result of the combined effect of low-penetrance genetic variants. As these are identified over the next several years, we can expect more insights into biology, and eventually perhaps the possibility of targeting interventions to the highest-risk groups.

When I first started publishing in cancer genetics, none of the predisposing genes had been identified. Now there are many high-penetrance genes, and the search for low-penetrance variants is well under way. This has all been driven by technological advances in DNA analysis, and more recently by the genome project. With it has come a predominant genetic perspective in thinking about cancer which was absent 30 years ago.

The big goal for the next 10 years is to elucidate the "genetic architecture" of the common cancers. That is, what is the mix of common and rare, and strong and weak, germline genetic variants involved with susceptibility? This mix will determine how easy the variants are to identify, and how quickly we can expect this type of genetic information to find practical application.

Professor Bruce Ponder, FRS
Cancer Research UK Department of Oncology
Hutchison/MRC Research Centre
Cambridge, England