BOSTON May 12, 1997 Mutations in the BRCA2 gene appear to be associated with fewer cases of breast cancer in young women than do mutations in the BRCA1 gene, according to a study appearing in the May 15 New England Journal of Medicine. The study, one of several in the issue that look at factors related to these so-called "breast cancer genes," was conducted by scientists at the Massachusetts General Hospital (MGH) Cancer Center and colleagues from Tohoku University in Japan and University of Texas Southwestern Medical Center in Dallas.
"Our results show just how complicated it can be to interpret the results of testing for mutations in these genes," says Daniel A. Haber, MD, PhD, director of the MGH Center for Cancer Risk Analysis, who led the study. "It isnt just a case of saying that a woman is or is not at increased risk; the risks may be quite different for women at different ages."
Identified in 1994 and 1995, respectively, the genes called BRCA1 and BRCA2, when mutated, appear to be strongly associated with inherited forms of breast cancer. BRCA1 mutations also are associated with increased risk for ovarian cancer. Although it has been estimated that up to 80 percent of women who inherit mutated forms of these genes will develop breast cancer in their lifetimes, the genes are associated with only 5 to 10 percent of overall cases of breast cancer and 5 percent of ovarian cancer.
Mutations in these genes clearly are associated with increases in lifetime breast cancer risks, but the implications for developing cancer at a certain age are less clear. Earlier studies by the MGH researchers have suggested that about 12 percent of women who develop breast cancer at an early age (40 or younger) have mutations in BRCA1.
To investigate the contribution of BRCA2 mutations to early-onset cancer, the MGH-led team screened blood samples from 73 women diagnosed with breast cancer at age 32 or younger for mutations in both the BRCA1 and BRCA2 genes. They also screened samples from 39 Jewish women diagnosed at age 40 or younger for three specific mutations two affecting BRCA1 and one affecting BRCA2 and compared the results with the previously determined prevalence of these mutations among people of Ashkenazi Jewish descent.
Among the 73 women diagnosed at or before age 32, only two had BRCA2 mutations (2.7 percent), compared with nine who had mutations in BRCA1 (12 percent, similar to the previous findings). Analysis of the samples from Jewish women showed that mutations in BRCA1 were 5 to 10 times more likely to be associated with early-onset breast cancer than were mutations in BRCA2.
The researchers note that their findings emphasize the need for caution in recommending that women with mutations in these genes take measures to prevent cancer development. Haber says, "Anyone making decisions about radical treatments such as removal of breasts or ovaries needs to consider a huge range of factors. And we still have many unanswered questions that can be answered only by clinically following those women who do get screened."
The MGH Center for Cancer Risk Analysis has assembled genetic data, blood and tissue samples from more than 420 women who developed breast cancer before the age of 40. Since discovery of the genes associated with inherited breast cancer, the centers researchers have used the materials to investigate the prevalence of mutations in these genes and their relationship to the actual occurrence of breast cancer.
Habers co-authors on the paper are Michael Krainer, MD, Sandra Silva-Arrieta, Michael FitzGerald, Deborah MacDonald, RN, MS, Hilal Unsal, MD, Dianne Finkelstein, PhD, and Kurt J. Isselbacher, MD, from the MGH; Akira Shimada, MD, Chikashi Ishioka, MD, Ryunosuke Kanamura, MD, from Tohoku University; and Anne Bowcock, PhD, from University of Texas Southwestern Medical Center.
The Massachusetts General Hospital, established in 1811, is the oldest and largest teaching hospital of the Harvard Medical School and conducts the largest hospital-based research program in the United States. The MGH has major research centers in transplantation biology, the neurosciences, cardiovascular research, cancer, cutaneous biology and photomedicine. Along with Brigham and Womens Hospital, the MGH is a founding member of Partners HealthCare System, Inc.
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