BioWorld International Correspondent

LONDON Once all the genes that contribute to a woman’s risk of breast cancer have been identified, geneticists will be able to target measures to prevent the disease in the subgroup of women among whom almost 90 percent of cases are likely to arise, researchers in Cambridge, UK, predict.

Their analysis suggests that it may be possible within a few years to offer women with a family history of breast cancer a test that will check for mutations in a range of genes, giving them a risk estimate based on their genetic makeup and paving the way for personalized prevention strategies.

The team reports its results in a paper in the March 3, 2002, Nature Genetics advance online publication titled “Polygenic susceptibility to breast cancer and implications for prevention.”

Douglas Easton, director of the Cancer Research UK Genetic Epidemiology Research Group at Strangeways Research Laboratory in Cambridge, which is linked to the University of Cambridge, told BioWorld International, “We have shown that genetic susceptibility to breast cancer can be explained by there being a large number of genes, each causing a small risk of breast cancer but adding together to give a distribution of risk in the population, so that some women are at much higher risk than others. If these genes can be identified, this should enable us to identify a small proportion of the population that is at substantial risk of developing the disease.”

Some researchers have taken the view that because most of the genes conferring a high risk of developing breast cancer when mutated have probably now been found, identifying the genes that contribute only a low risk is unlikely to have a large practical impact on clinical management of women concerned about their risk of breast cancer. Easton believes, however, that this view is mistaken. “We would argue that once all or most of these low-risk genes have been found, when their effect is combined, the variation in risk between women who have few of them compared with women who have many of them is likely to be substantial,” he said.

Easton and his colleagues began their study by examining a series of models of the genetics of breast cancer. These ranged from there being just a single gene BRCA3 in addition to BRCA1 and BRCA2 (the latter two already being known to confer high risk of breast cancer), to models in which many other genes contributed to breast cancer risk.

They then looked at several series of breast cancer patients, including families with several members affected, to see which of the models best fit the epidemiological data. They found that the model that gave the best fit with the natural occurrence of the disease was the polygenic model, one in which there were several genes contributing to risk of breast cancer, in addition to BRCA1 and BRCA2.

Easton said, “We can tell that this is likely to be the case, because families with BRCA1 and BRCA2 usually have many cases of the disease. If a family with, say, six cases of breast cancer comes forward, there is a strong likelihood that it will be due to one of these two genes. This suggests that other genes with such a strong effect are either nonexistent or rare. Nevertheless, families with two to three cases of breast cancer are very common, and not usually explained by BRCA1 and BRCA2. So this fits with the model in which there are several other genes, which are probably commoner and individually causing a lower risk.”

Furthermore, Easton said, if there were, say, just one other gene causing breast cancer, researchers would probably have identified it by now by genetic linkage studies.

The finding has many implications for prevention, Easton said. In the future, once the genes contributing to a woman’s polygenic risk of breast cancer are known, much better predictions could be made of her personal risk of developing the disease than are currently available by examining lifestyle factors such as reproductive history or age at menopause.

“We calculate that 88 percent of cases of breast cancer are going to occur in the 50 percent of the population who are at the highest genetic risk, while only 12 percent of cases will occur among the 50 percent of individuals who are at lowest genetic risk,” he said. “So you could imagine that if there are interventions that could be developed that substantially reduce the risk of breast cancer but which clinicians are not happy to give to the whole population because of side effects such as toxicity, these could be targeted at a subset of the population that is at highest risk.”

The main program of work at Strangeways Research Laboratories is to identify the remaining genes that play a role in breast cancer risk. Several studies involve examining DNA samples from many patients with breast cancer, looking for polymorphisms in genes that are known to be relevant to cancer development, and comparing the frequency of these small variations in people with cancer and the general population.