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Two Genetic Variants Raise Risk of Breast Cancer

Contact: 
Gwen Ericson
ericsong@wustl.edu 
314-286-0141

April 2, 2009 – A multicenter study has found two new genetic variants associated with an increased risk of breast cancer. The study was conducted by the Cancer Genetic Markers of Susceptibility (CGEMS) initiative and reported through advance online publication this week in Nature Genetics.

"Each of these markers independently increases a woman's risk of breast cancer," says one of the study's investigators, Graham Colditz, MD, DrPH, associate director of prevention and control at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. "The increased risk is fairly small – comparable to the increased risk represented by such factors as being overweight or lacking physical activity."

A number of environmental and lifestyle factors can raise the risk of breast cancer to varying degrees. These include current use of oral contraceptives or hormone-replacement therapy, alcohol consumption, being overweight and lack of physical activity. A woman's genetic makeup also contributes to the likelihood of developing breast cancer, and the disease is nearly twice as frequent in women who have a close relative with breast cancer.

In the United States, the average lifetime risk of breast cancer for women is about 13 percent, so the 20 percent to 30 percent risk increase represented by the new genetic variants would raise the lifetime risk for a woman who carries one of the variants to about 16 percent or 17 percent. In comparison, well-known high-risk genetic variants in the BRCA1 and BRCA2 genes raise a woman's risk of breast cancer by 300 percent to 700 percent. In addition to uncovering the two new risk variants, the study confirmed that six previously discovered variants were associated with increased risk of breast cancer.

Colditz indicates that the newly identified genetic variants, along with those previously discovered, can potentially help doctors evaluate risk in patients who have additional breast cancer risk factors associated with their physical health and lifestyle. The genes can also provide information that can lead to new strategies for prevention or treatment.

The current study used genomewide association analysis to look for genetic variants that raise breast cancer risk. Genomewide association involves scanning genetic markers in the complete sets of DNA, or genomes, of many people to find genetic variations associated with disease. The researchers compared the genomes of almost 10,000 postmenopausal women with breast cancer to an equal number without breast cancer. The two newly identified risk variants were significantly more frequent in women with breast cancer than in those without disease.

One of the variants, present in about 39 percent of women, was on chromosome 1. The variant is in a genetic region near the centromere, a structure near a chromosome's middle that is important during cell division. Two known genes reside in the region, and at this time, it is not clear whether these or other nearby genes might be associated with breast cancer risk. The other variant, present in 76 percent of women, was on chromosome 14 in a gene called RAD51L1, which is involved in repairing damaged DNA.

The authors suggest that the new associations could point to previously unknown cellular pathways that contribute to breast cancer development, but they also indicate that the clinical significance of the genetic locations still need to be determined with further research.


Thomas G, et al. A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nature Genetics. March 29, 2009 (advance online publication).

Funding from the National Institutes of Health supported this research.