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.