Breast Cancer Susceptibility Genes Pile Up

A large genome-wide association analysis has revealed 15 more SNPs associated with breast cancer. The work, published in Nature Genetics, brings to 94 the number of SNPs identified to date for the disease, and offers additional potential genetic markers for risk analysis.

Previous large-scale genetic studies implicated 79 loci in breast cancer, accounting for approximately 14% of the inherited disease risk. To find more, researchers from the Breast Cancer Association Consortium and the Collaborative Oncological Gene-environment Study pooled data from more than 120,000 women of European ancestry genotyped for more than 200,000 common SNPs. About 11.6 million additional SNPs were imputed based on published genomic data.

The effort confirmed 71 of the previously reported SNPs and uncovered 15 new variants that slightly increased or decreased breast cancer risk. Although the effect of any one SNP is extremely small, together they multiply risk. The data indicate that 5% of women inherit a combination of variants that at least double their lifetime risk of breast cancer, and 0.7% inherit a tripled risk.

Taken in aggregate, the known SNPs contribute as much to breast cancer as rare mutations in high-risk genes such as BRCA1 and BRCA2, says D. Gareth Evans, MD, FRCP, of the University of Manchester in England, who was not involved in the study. The difference is that the variants provide a means to assess risk for all women, Evans says, whether or not they carry BRCA or other rare mutations.

“In the next few years it should be possible to develop tests covering over a hundred SNPs, and marry that data together with other risk factors to come up with a pretty accurate assessment of any woman's risk for breast cancer and at what age she is likely to get it,” Evans says. “We can then target screening and preventive measures much more accurately.”

Just how the SNPs affect breast cancer development remains to be determined. “There is a lot of work to do to understand the function and to work out if any of the genes are targets of drugs or can lead to mechanistic understanding,” says study leader Douglas F. Easton, PhD, of the University of Cambridge in England.

Altogether, known SNPs now account for about 16% of the genetic risk, which means there are still more to be discovered. To that end, researchers are undertaking an even larger study, the OncoArray project, with double the number of subjects and more SNPs. Easton says they expect to find more loci, and glean more detail on known loci, which should yield data next year.