Diagnostics & Imaging Week Correspondent

LONDON — Almost three of four women of European descent have a gene variant that increases their risk of breast cancer by a very small amount.

The rest have a variant of the same gene that reduces their risk of breast cancer by 10% or more.

Ultimately, understanding how the protein product of the gene concerned — which is known as CASP8 — affects the development of breast cancer could lead to new treatments for the disease.

More immediately, the discovery brings closer the day when physicians will be able to offer all women a genetic screen that will provide personalized predictions of their risk of breast cancer.

Michael Stratton, a member of the Breast Cancer Association Consortium from the Institute of Cancer Research in Sutton, UK, told Diagnostics & Imaging Week’s sister publication BioWorld International: “This is the first discovery of one of the common variants that causes a small increase in breast cancer susceptibility. There have been many reports of such variants in the past, which have turned out to be incorrect, but the size of this study allows us to be certain that this is a real effect.”

Stratton explained that although the additional risk associated with inheritance of the common variant of CASP8 is small, because it is so common, it will account for many cases of breast cancer worldwide.

“As a result, if we could find a way of somehow interfering with this susceptibility allele, then this might have some effect on breast cancer incidence,” he said.

Paul Pharaoh, also a member of the consortium and a senior clinical research fellow at the University of Cambridge, aid: “We calculate that 0.3% of the genetic component of breast cancer is due to this gene in European populations.”

The consortium reports its results in a paper in Nature Genetics (Feb. 11) titled: “A common coding variant in CASP8 is associated with breast cancer risk”. The first author is Angela Cox of Sheffield University Medical School in Sheffield, UK.

For the study, the consortium pooled data from up to 15 studies that provided genetic information on more than 18,000 cases and almost 23,000 controls. The researchers were looking for evidence of an altered risk of breast cancer associated with each of 9 different gene variants that are common in the population (single nucleotide polymorphisms or SNPs). Studies had previously suggested that these gene variants were associated with an altered risk of breast cancer.

As reported in Nature Genetics, they found no conclusive evidence for an association with breast cancer for 8 out of the 9 variants. For the ninth variant, that in CASP8, there was a statistically significant reduction in the risk of breast cancer.

The study found that 26% of women carry one copy of the variant in CASP8, and that they were at 10% lower risk of developing breast cancer compared to women who did not carry this variant. Women who carry two copies of the variant in question (about 2% of the population) are even less likely to develop breast cancer, with a relative risk of 0.81.

CASP8 is known to be involved in apoptosis (programmed cell death). Nothing is known, however, about how the SNP associated with the change in breast cancer risk affects the functioning of the protein product of CASP8. The researchers also need to carry out studies to determine whether it is the SNP itself that is responsible for the observed effect, or whether the influence is due to another gene or part of a gene that is commonly inherited with the SNP.

Stratton said: “We need to carry out further work on this variant and understand what it does to the process of apoptosis. By observing what effect increasing or decreasing apoptosis through CASP8 has on the development of breast cancer, this variant may tell us what our strategies ought to be in order to reduce breast cancer, and possibly treat it as well.”

The consortium is now carrying out a genome-wide screen on similar numbers of women with breast cancer, and controls, in order to detect more genes that play a role in the development of breast cancer. Stratton expects that tens if not hundreds more genes will be identified by this strategy, with the results due “within a few months”.