A consortium of breast cancer researchers reports that a variation in the gene caspase-8 (CASP8) may offer modest protection against the disease. This is the first common genetic variant to be definitively linked to breast cancer, and the researchers believe many others will follow in the years ahead.

The Breast Cancer Association Consortium (BCAC), an international group of about 20 research teams that includes scientists from NCI, made the discovery. Formed in 2005, the Consortium examines genetic associations reported in the scientific literature by pooling data from many studies, including unpublished findings.

The findings appeared online in Nature Genetics on February 11.

To assess CASP8, the researchers used data on 33,000 women from 14 studies. They found an 11-percent reduction in breast cancer risk among women with a single CASP8 variant, and a 26-percent reduction among women with two copies of the variant.

"Our results indicate that, while many reported genetic associations are spurious false-positives, some associations can be substantiated given a sufficiently large study," says Dr. Douglas F. Easton of Cancer Research UK Genetic Epidemiology Unit and a Consortium leader.

Mutations in genes such as BRCA1 account for less than 25 percent of the inherited risk of breast cancer. The remainder likely comes from more common genetic variants that individually confer relatively small amounts of risk.

Such variants are thought to play a role in many common diseases. But most single epidemiological studies lack the statistical power required to identify them.

"This study provides proof of principle that consortia like the BCAC are valuable for understanding the contributions of genetic factors in complex diseases," says Dr. Montserrat Garcia-Closas of NCI's Division of Cancer Epidemiology and Genetics and a lead author.

To date, the Consortium has examined about 20 single nucleotide polymorphisms (SNPs). SNPs are locations in the genome where a single unit of DNA may vary from one person to the next.

The researchers caution that epidemiological data cannot prove that the SNP in CASP8, called D302H, is causing the reduced risk. They are investigating nearby variants, as well.

D302H is estimated to be present in 13 percent of women of white European ancestry. The new results will lead to studies of CASP8 in other ethnic groups.

The report has no immediate implications for women. But it suggests that researchers could use the same approach to identify panels of common genetic variants that collectively influence a woman's risk.

"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," says Dr. Garcia-Closas. 

CASP8 is involved in programmed cell death, a defense mechanism that allows cells to commit suicide rather than develop into a tumor. One hypothesis about D302H is that the variant may enhance the body's ability to clear cancerous cells.

The Consortium examined other genes, as well. They found some support for an association between breast cancer risk and a variant in the transforming growth factor gene TGFB1, which helps regulate the growth of cells, among other things.

Numerous variants are likely to be identified in the coming years from genome-wide association studies, says Dr. Jeffery P. Struewing in the Laboratory of Population Genetics at NCI's Center for Cancer Research and a co-author on the study.

Given how few genes have been examined in depth to date, Dr. Easton predicts that large numbers of breast cancer susceptibility variants will eventually be found.

"International collaboration is absolutely essential for these association studies to be successful," he adds. This study included women from 13 countries.

By Edward R. Winstead