Researchers have identified genetic variations in a region of DNA that may be associated with risk for breast cancer. Women with the variation have a 1.4 times greater risk of developing breast cancer compared to those without this variation.

The study is one of several genome-wide association studies looking for breast cancer genes to be published this year by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, and their colleagues. These findings appeared online in the "Proceedings of the National Academy of Sciences" on March 3, 2008.

"A genome-wide association study looks at the entire genome for a type of genetic variation that occurs more frequently in people who have a certain disease than in similar people who do not have the disease," said Bert Gold, of NCI's Center for Cancer Research, the study's lead author. "Using this research approach, we found variations in a gene locus, a specific place on a chromosome where a gene is located, that had not been identified in previous studies."

Genome-wide association studies look for genetic variations known as single nucleotide polymorphisms (SNP). SNPs are alterations in the genetic code in which a single nucleotide - the individual building blocks that make up DNA - is changed. The researchers found that variations in four SNPs located in a region of chromosome 6 were present more often in the breast cancer patients, suggesting that genes in this region might contribute to the risk of breast cancer. The researchers also confirmed the finding of previous studies indicating that the locus named FGFR2 is associated with a 20 per cent increased risk of breast cancer.

"The likelihood that this finding could be due to chance alone is about one in 300 million," said Gold. "We have already begun experiments to try to identify the genes associated with risk, and then try to characterize their function. It is hoped that identifying the genes responsible for this increased risk may lead to new therapies that target the actions of these genes."

"Progressing from genome-wide association studies to the development of therapies and enhanced diagnostic techniques based on those findings will require continued, sustained effort from laboratory researchers who will unite our newfound knowledge of the genome with the study of cancer biology," said NCI director John E. Niederhuber.

Several genes located in this chromosome region play a role in regulating important cell processes, such as cell cycle, DNA replication and repair, cell signalling, and programmed cell death. Defects in these processes have been well documented in breast cancer.

While the variations in chromosome 6 that increase risk for breast cancer were found in 23 per cent of the women studied, their risk of developing breast cancer is relatively small compared to the high-risk associated with BRCA gene mutations. BRCA genes were identified in the 1990s and mutations in these genes are among the strongest known genetic risk factors for breast cancer. The researchers estimate that only about seven percent of breast cancer cases in this current study could be attributed to the locus they found on chromosome 6.

"Although identifying individual low risk loci may have limited clinical implications, it is not known whether interactions among multiple loci will put a woman at greater risk of developing breast cancer," said Gold. "A better understanding of the genetic mutations that contribute to breast cancer is likely to come from the identification of these low risk variants and from studies that investigate the mechanisms underlying their associations."

The researchers conducted a three-phase genome-wide association study to look for SNPs that may be associated with breast cancer risk. In the first phase, they analyzed more than 150,000 SNPs in DNA samples obtained from 249 Ashkenazi Jewish women who had breast cancer and a family history of the disease but did not carry the BRAC1 or BRAC 2 mutation and from 299 Ashkenazi Jewish women who had not developed cancer. They studied Ashkenazi Jewish women because many studies have demonstrated that this population has been associated with an increased breast cancer risk compared to other populations. In the next two phases, the researchers verified their findings in 950 Ashkenazi Jewish women with breast cancer and 979 Ashkenazi Jewish women who did not have cancer as well as in a set of 243 Ashkenazi Jewish women who had sporadic breast cancer and 187 cancer-free Ashkenazi Jewish women.