Genetic tests to id risk of breast cancer

In spite of Myriad Genetic's patents on the BRCA1 and BRCA2 genes having a widely reported chilling effect on research in this area, some scientists have continued to work on the genetic predisposition to develop breast cancer.

Cambridge researchers say there are seven common gene sites that elucidate the risk of developing cancer. From the Independent today:

"The chances of getting breast cancer vary more than sixfold among women because of their genetic inheritance but the breast screening programme fails to target those at highest risk, scientists have found. Researchers at the University of Cambridge say it may soon be possible to offer women a genetic test based on the seven common gene sites that determine cancer risk and to focus prevention efforts accordingly.

Currently doctors only test women with a very strong family history of breast cancer for the high-risk genes such as BRCA1 and BRCA2. These gene faults increase the chances of a woman developing cancer from around 9 per cent to 80 per cent. But they are rare and few women benefit from such testing.

There are other common genetic variations that modestly increase the risk – but when they occur together they have a substantial effect. Around 3,300 women in the UK carry the low risk genes for each of the seven gene sites identified, who have less than half the risk of breast cancer of the general population – a 4.2 per cent lifetime risk compared with a 9.4 per cent risk.

At the other end of the scale, around 400 women have high risk genes for each of the seven sites, giving them a 23 per cent risk of developing breast cancer – two and a half times that of the population as a whole."

From the original study published in the New England Journal of Medicine this week:

"Background New developments in the search for susceptibility alleles in complex disorders provide support for the possibility of a polygenic approach to the prevention and treatment of common diseases.

Methods We examined the implications, both for individualized disease prevention and for public health policy, of findings concerning the risk of breast cancer that are based on common genetic variation.

Results Our analysis suggests that the risk profile generated by the known, common, moderate-risk alleles does not provide sufficient discrimination to warrant individualized prevention. However, useful risk stratification may be possible in the context of programs for disease prevention in the general population.

Conclusions The clinical use of single, common, low-penetrance genes is limited, but a few susceptibility alleles may distinguish women who are at high risk for breast cancer from those who are at low risk, particularly in the context of population screening...

Although the clinical use of single, common low-penetrance genes is limited, a small number of susceptibility alleles could distinguish women at high risk for breast cancer from women at low risk, particularly in the context of population-screening programs. Moreover, stratifying women according to genetic risk may improve the efficiency of screening programs.

There are many questions to be answered and barriers to be overcome, however, before such potential could be realized. The simple models we described make several assumptions, some of which may not be robust. For example, the assumption that the benefit of mammographic screening for an individual woman is merely a function of absolute risk is clearly an oversimplification. The sensitivity of mammography is reduced in women younger than 50 years of age, and the true benefit is more likely to be a complex interaction between age and absolute risk. Furthermore, the complexity of a population-oriented prevention program that is based on individual risk might outweigh its marginal improvement in efficiency. As more risk alleles are identified, however, our ability to predict risk will improve, and the gain in efficiency will increase.

If it were feasible to implement a program for women with a genetic risk of breast cancer, public (and professional) education would be necessary, and even then the concept might not be acceptable. However, new and expensive forms of screening or screening tests with marginal clinical benefits to the individual woman may be possible only in subgroups of the population at high risk. Screening for breast cancer by means of MRI may be more effective than mammography, but it would be prohibitively expensive unless it was targeted to patients at highest risk.

Effective use of genetic profiling depends on the best available set of markers. Most reported genetic associations have been false positive results and would be worthless for risk prediction.³¹ The evidence providing support for some loci that were recently identified in genomewide studies, such as those used in the above calculations, is strong, but it will still be important to base profiling on accurate estimates of the risks associated with these loci, either singly or in combination.

Our understanding of the genetic susceptibility to breast cancer and other complex diseases is likely to change rapidly over the next decade. Policymakers should start to consider how this knowledge could be used to make a polygenic approach to disease prevention a reality."

It's a challenging but rewarding read and at a little over 3000 words is relatively brief. In addition, you're always likely to get a more accurate picture of what the scientists have discovered through reading the actual paper rather than the mass media's interpretation of the research. (Note that I'm not a geneticist but an 'allele', as I understand it, is one variety of a series of possible alternative forms of a particular gene. So with the gene controlling eye colour, for example, one allele could be the code for blue eyes, another the code for brown eyes.)