New York, September 1, 1998-- A new genetic mutation has been found to modestly increase the risk of hereditary breast cancer in women of Ashkenazi Jewish descent but has an especially pronounced effect in those who already carry the other well-known BRCA mutations linked to the disease, report scientists at Memorial Sloan-Kettering Cancer Center and other research centers in the September issue of Nature Genetics. The findings indicate that the new mutation may serve as the first genetic modifier of breast cancer risk observed in women who are already susceptible to hereditary breast cancer.
"While we found the overall risk in inherited breast cancer linked to the APC mutation to be elevated, the increase was most significant in the women who had BRCA mutations," says Dr. Kenneth Offit, Chief of the Clinical Genetics Service at Memorial Sloan-Kettering and senior author of the study.
The study shows that the mutation called APC I1307K, increases the risk of inherited breast cancer by 50 percent in women of Ashkenazi Jewish descent, which translates to about a 15 percent lifetime breast cancer risk for this group of women with the APC mutation as compared to a breast cancer risk of about 10 percent for all women in the general population.
The current study estimate is based on blood samples drawn from a group of women of Ashkenazi Jewish descent with breast cancer who were compared to a control group of women of the same ethnic background without breast cancer. The study was conducted by investigators from Memorial Sloan-Kettering in collaboration with investigators from the University of Toronto in Ontario, McGill University in Montreal, Canada and other research centers.
In one group, 632 women with breast cancer were selected without regard to a family history of the disease. The APC mutation was detected in 10.1 percent of the women in this group. Of those who were found to have BRCA mutations, the prevalence of the APC mutation was even greater -- ranging upward to 19 percent. As a comparison, the mutation was observed in about 7 percent of 4,635 women of Ashkenazi Jewish descent who did not have breast cancer. These healthy women were participating in a separate genetic epidemiology study conducted by researchers from the National Institutes of Health and reported in the same issue of Nature Genetics.
Although mutations in the BRCA genes are the most well-known links to breast cancer, a previous study showed that the APC gene mutation was linked to an increased risk of developing colon cancer. In that study, published in the September 1997 issue of Nature Genetics, some of the individuals with colon cancer also had a family history of breast cancer. This led Dr. Offit's group to question whether the APC mutation might appear more frequently in those women with breast cancer. To find out, the investigators studied the frequency of the mutation in women with breast cancer and found that the increased breast cancer risk associated with the APC mutation was further elevated when any of the BRCA mutations were present.
While this finding indicates that the APC gene mutation could be one of the first genetic modifiers of breast cancer risk in women already at hereditary risk for breast cancer, the researchers also found that the women who had the mutation did not develop breast cancer at an earlier age.
"Despite considerable interest, we caution against testing for the APC mutation outside of research trials, as the effect is not yet significant enough to justify clinical intervention," says Dr. Offit, who notes that inherited breast cancer only accounts for 5 to 10 percent of all breast cancers.
Memorial Sloan-Kettering Cancer Center is the world's oldest and largest institution devoted to prevention, patient care, research, and education in cancer. Throughout its long, distinguished history, the Center has played a leadership role in defining the standards of care for patients with cancer. In 1998, Memorial Sloan-Kettering was named the nation's best cancer center for the sixth consecutive year by U.S. News & World Report.
Journal
Nature Genetics