Newly identified inherited variants of a single gene increase breast cancer risk for women of European ancestry approximately 20 percent if they carry one copy of the gene and by 60 percent if they carry two copies. These variants, in the FGFR2 (Fibroblast Growth Factor Receptor 2) gene, were found in more than half of the women studied.

The discovery appears to be the most important breast cancer-associated gene since BRCA1 and BRCA2 were identified in the 1990s. The variants in FGFR2 were initially associated with postmenopausal breast cancer and then confirmed in premenopausal women. Inherited mutations in the BRCA genes are much less common in the population.

The discovery was made by a team that includes researchers from the Harvard School of Public Health (HSPH), Brigham and Women’s Hospital (BWH), and the U.S. National Cancer Institute (NCI), working with collaborators from the NCI Breast Cancer Cohort Consortium.

An association between variants in the FGFR2 gene and breast cancer risk was also identified by a larger international consortium based at the University of Cambridge. That study identified several additional breast cancer susceptibility genes and is available on the Nature Web site. HSPH Professor and BWH epidemiologist David Hunter is lead author of the Nature Genetics paper and a co-author of the Nature paper.

Scientists have recognized that family history is a strong predictor of breast cancer risk, but the culprit genes identified so far fall far short of accounting for all breast cancer risk. The two most well-known genes associated with breast cancer – BRCA1 and BRCA2 – are carried by a very small percentage of the U.S. population and are found in women with a very strong family history of the disease. A combination of other genetic factors, each contributing smaller degrees of additional risk, is presumed to account for most of the inherited genetic component of risk of breast cancer.

The FGFR2 variants now associated with breast cancer risk are estimated to be present in more than 60 percent of U.S. female adults. The gene variants appear to be involved in the control of cell growth or division, but the precise mechanism by which they act requires further research.

“This finding opens up new avenues of research into the causes and prevention of breast cancer by identifying a new biological pathway relevant to risk of the disease,” said Hunter, who is a professor in cancer prevention at HSPH.

The researchers conducted a genome-wide association study using blood samples from 1,145 postmenopausal women enrolled in the Nurses’ Health Study, based at the Brigham and Women’s Hospital, who had developed invasive breast cancer. These samples were compared to those taken from 1,142 women who had not developed cancer. The study participants identified themselves as being of European descent.

In each DNA sample, more than 528,000 gene variants, or single nucleotide polymorphisms (SNPs), were examined to see if they were associated with breast cancer. Eight leading candidates emerged. Those eight were further tested in samples from 1,776 women with breast cancer and 2,072 healthy women in three prospective cohorts: the Nurses’ Health Study II, which included premenopausal women; the Prostate, Lung, Colorectal, and Ovary Cancer Screening Trial; and the American Cancer Society Cancer Prevention Study-II. In these studies, the four related gene variants of FGFR2 were confirmed.

“It is premature to recommend screening women for these gene variants, at least until the scientific community has further combed through the genome-wide findings and found all the variants that are associated with increased risk,” said Hunter.