In a study involving more than 31,000 women with cancer-causing mutations in the BRCA1 or BRCA2 genes, researchers at The Basser Center for BRCA, the Abramson Cancer Center, and the Perelman School of Medicine at the University of Pennsylvania identified mutations that are associated with significantly different risks of breast and ovarian cancers. Authors say the results - which show that some mutations confer higher risks of breast cancer, while other mutations show higher risks of ovarian cancer - may lead to more effective cancer risk assessment, care and prevention strategies for health care providers and carriers. The results are published in the April 7 issue of JAMA.

“We’ve made a lot of progress toward understanding how to reduce the cancer risks associated with inherited mutations in BRCA1 or BRCA2 mutations, but until now, little has been known about how cancer risks differ by the specific mutation a woman has inherited,” said Timothy R. Rebbeck, PhD, professor of Epidemiology, and associate director for Population Science at Penn Medicine’s Abramson Cancer Center. “The results of this study are a first step in understanding how to personalize risk assessment around a woman’s specific mutation, which can help guide carriers and providers in the cancer prevention decision making process.”

Rebbeck and colleagues evaluated cancer diagnoses for 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations. The team then analyzed whether the BRCA1 and BRCA2 mutation type or location was correlated to breast and/or ovarian cancer risk. He and his co-authors identified regions of both BRCA1 and BRCA2 that, when mutated, confer higher risks of ovarian cancer, and other regions that confer higher risk of breast cancer.

Previously, a woman with a BRCA1 mutation would have been thought to have a 59 percent risk of breast cancer and a 34 percent risk for ovarian cancer, up until age 70. However, the new research suggests that women who carry a specific subset of BRCA mutations most commonly present in the Ashkenazi Jewish population have a higher risk of breast cancer (69 percent) and a lower risk of ovarian cancer (26 percent), for example. The important question that remains is whether these differences will change the decisions a woman makes about preventive surgery or other behaviors.

“With these new findings, we’ve gained knowledge of mutation-specific risks which could provide important information for risk assessment among BRCA1/2 mutation carriers,” said senior author Katherine L. Nathanson, MD, associate professor of Medicine and director of Genetics in the Basser Research Center for BRCA at Penn’s Abramson Cancer Center, “Additional research is needed to determine the absolute risks associated with different mutations, and how those differences might influence decision making and standards of care, such as preventive surgery, for carriers of BRCA1 and BRCA2 mutations.”

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In addition to Rebbeck and Nathanson, other Penn authors on the study include Nandita Mitra, PhD, and Fei Wan, MS, from the Center for Clinical Epidemiology and Biostatistics, and Susan M. Domchek, MD, executive director of the Basser Center for BRCA.

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4.9 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $409 million awarded in the 2014 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania - recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital - the nation’s first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2014, Penn Medicine provided $771 million to benefit our community.

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Katie Delach
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University of Pennsylvania School of Medicine