Variation in gene caspase-8 may help protect against breast cancer

A large-scale analysis of data on breast cancer risk has concluded that a common variation in the gene caspase-8 (CASP8) is associated with a somewhat lower risk of the disease. Variants are small changes that occur in a gene sequence.

The results are from the second study published by the Breast Cancer Association Consortium (BCAC), which includes researchers at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH).

"The consortium, which was launched in 2005, has helped speed the discovery of genes and variants involved in breast cancer through the pooling of data from many studies and should prove invaluable to future research studies that explore the genetic aspects of cancer," said NIH Director Elias A. Zerhouni, M.D.

The results were published in the February 11, 2007 issue of Nature Genetics. "This study demonstrates how genes that confer modest effects on breast cancer risk can be identified when sufficiently large data sets are assembled," said NCI Director John E Niederhuber, M.D. "Analyses of this type should help accelerate our ability to target the right genes for very specific subsets of disease."

Mutations in genes with large effects on breast cancer risk have been identified, yet most single population-based studies lack the statistical power to detect more common variations in genes that contribute only small amounts to breast cancer risk. To confirm a previously identified association with a variant of the CASP8 gene, for example, the Consortium used data on 33,000 women from 14 studies.

The researchers say that the new findings have no immediate implications for women. "But using the same approach we may be able, in the future, to identify a panel of variants with small increases in risk that collectively may put a woman at a much higher risk," says Montserrat Garcia-Closas, M.D., Dr.P.H., of NCI's Division of Cancer Epidemiology and Genetics and one of the study's lead authors.

"This study provides proof of principle that consortia like the BCAC are valuable for understanding the contributions of genetic factors in complex diseases. A better understanding of the biology of breast cancer is likely to come from the identification of these variants and future studies that investigate the mechanisms underlying the associations," she adds.

To date, the BCAC has evaluated about 20 single nucleotide polymorphisms (SNPs), the most common type of gene variant in which a single unit of DNA may vary from one person to the next. Each SNP investigated has been linked to breast cancer risk by at least two studies that included more than 10,000 individuals. The BCAC uses essentially all the available data on a SNP, including unpublished results, to either confirm or refute an association.

Two previous studies suggested that a SNP in CASP8, called D302H, is associated with a reduction in breast cancer risk. The researchers caution that population-based data alone cannot prove that this particular variant is responsible for the association. Other studies are underway to determine whether D302H or another variant nearby might be responsible.

Most of the 14 studies that contributed data to the Consortium's analysis included women of predominantly white European ancestry. The variant is estimated to be present in 13 percent of white women of European descent. (The variant was not present in two Asian populations studied.) Garcia-Closas said that, based on this study, researchers will likely assess the D302H polymorphism and other variants in the CASP8 gene in other ethnic groups.

Future studies will also investigate the biology of how variation in this gene may protect against the disease. The protein produced by the CASP8 gene participates in programmed cell death, or apoptosis, a defense mechanism that allows cells to commit suicide rather than develop into a tumor. DNA damage can trigger apoptosis, and one hypothesis is that the CASP8 SNP may enhance the body's ability to clear cancerous cells from the body and thereby lower the risk of breast cancer.

While mutations in some genes such as BRCA1 have previously been linked to cancer risk, the genetic variation found in the CASP8 gene is the first common variant to be definitively associated with breast cancer risk. In addition to this variant, the study found some support for an association with breast cancer risk for a variant in the gene TGFB1(Transforming Growth Factor Beta 1). Numerous other variants are likely to be identified in the coming years from genome-wide association studies, said Jeffery P. Struewing, M.D., senior investigator in the Laboratory of Population Genetics at NCI's Center for Cancer Research and a coauthor of the current study.

Effective strategies for finding variants in genes that contribute modestly to breast cancer risk are needed. Mutations in genes such as BRCA1 or BRCA2 account for less than 25 percent of the excess familial risk of breast cancer. Much of the remaining variation in genetic risk is likely to be explained by the cumulative effect of multiple variants in genes that individually confer relatively small amounts of risk.

"The SNPs in CASP8, and perhaps in TGFB1, are the first examples of such variants," said Douglas F. Easton, Ph.D. of Cancer Research United Kingdom Genetic Epidemiology Unit, one of the leaders of the BCAC. "Given that only a small number of genes have been investigated in this depth, the results suggest that large numbers of breast cancer susceptibility variants will eventually be found."