Researchers have identified new genetic variations in two regions of DNA -- located on chromosomes 1 and 14 -- that may be associated with the risk of sporadic breast cancer. This study also confirms some of the previously identified associations between specific regions in the genome and breast cancer risk. The findings are reported by the Cancer Genetic Markers of Susceptibility (CGEMS) team, which includes researchers at the National Cancer Institute (NCI), part of the National Institutes of Health. The study appeared online on March 29, 2009, in Nature Genetics.

Nearly every cell in the human body contains 46 chromosomes -- tightly packed bundles of DNA, half which came from each parent. While the DNA of any two people is more than 99 percent the same, the fraction of DNA that varies among individuals can play an important role in risk of disease. The most common type of variation, called a single nucleotide polymorphism (SNP), affects just a single building block of DNA. SNPs are used in genome-wide association studies to identify chromosome regions that are associated with disease.

"By studying large populations of individuals with and without disease, CGEMS research can provide powerful indicators as to which SNP variations are associated with breast cancer," said Stephen Chanock, M.D., director of NCI's Core Genotyping Facility and chief of the Laboratory of Translational Genomics in the Division of Cancer Epidemiology and Genetics (DCEG). "The two new regions identified in our study open up great possibilities for research into novel pathways contributing to the development of breast cancer. In turn, an in-depth understanding of the biology underlying the contribution of these genetic variations could one day lead to new approaches for therapy or prevention of breast cancer."

"Breast cancer is a complex disease, and it is important to recognize that multiple genetic alterations will be involved in predicting risk and prognosis, leading to treatment. The important next step will be to take this association of risk and, through further research, link these specific genetic defects to changes in biologic function," said NCI Director John E Niederhuber. "By understanding altered genetic pathways, we will ultimately be able to turn knowledge of genetic variations and risk into novel targets for drug development, which may enhance our ability to prevent and/or control this disease."

The region identified on chromosome one contained the rs11249433 SNP. Although the function of this SNP is unknown, further analysis by the CGEMS team found that this region is predominately associated with estrogen receptor-positive breast cancer, the most common molecular subtype of breast cancer.

The newly identified region found on chromosome 14, which included the rs999737 SNP, is located near an interesting gene, RAD51L1, which is in a pathway previously implicated in breast cancer risk. The protein encoded by this gene interacts directly with those of other genes that are involved in DNA repair and in the exchange of material between strands of DNA.

The researchers also confirmed previous reports that six other genomic regions -- located on chromosomes 2, 5, 8, 10, and 16 -- are associated with breast cancer risk. Further study of these regions may help to identify possible mechanisms that may contribute to the development of breast cancer.

"We have known for over a decade about a few genes that predispose women to risk of breast cancer," said Chanock. "But, through studies like CGEMS, we're increasing the catalog of regions in the genome that contribute to breast cancer risk."

In addition to Chanock, CGEMS is co-led by Joseph Fraumeni Jr, Gilles Thomas and Robert Hoover also of NCI's DCEG; Daniela Gerhard of NCI's Office of Cancer Genomics; and David Hunter, from the Harvard School of Public Health, Boston, Mass. The success of the CGEMS project is based on a collaboration between epidemiologists, biostatisticians, and genomic scientists at NCI and at several other research institutions, funded through grants from NCI, who together have analyzed DNA from thousands of cases and controls drawn from NCI-supported studies of both breast cancer and prostate cancer.

The CGEMS team conducted a three-stage genome-wide association study in women of European ancestry to identify SNPs that were associated with breast cancer.

NCI leads the National Cancer Programme and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers.