Inherited mutations in the BRCA1 gene and closely related BRCA2 gene account for about 5 to 10 percent of all breast cancers and 15 percent of ovarian cancers . For any given individual, the likelihood that one of these mutations is responsible goes up significantly in the presence of a strong family history of developing such cancers at a relatively early age. Recently, actress Angelina Jolie revealed that she’d had her ovaries removed to reduce her risk of ovarian cancer—news that follows her courageous disclosure a couple of years ago that she’d undergone a prophylactic double mastectomy after learning she’d inherited a mutated version of BRCA1.
As life-saving as genetic testing and preventive surgery may be for certain individuals, it remains unclear exactly which women with BRCA1/2 mutations stand to benefit from these drastic measures. For example, it’s been estimated that about 65 percent of women born with a BRCA1 mutation will develop invasive breast cancer over the course of their lives—which means approximately 35 percent will not. How can women in this situation be provided with more precise, individualized guidance on cancer prevention? An international team, led by NIH-funded researchers at the University of Pennsylvania, recently took an important first step towards answering that complex question.
In a study published in the journal JAMA, the researchers analyzed genetic data and health information from more than 31,000 women with mutations in BRCA1/2. They found that among such women, the answer to whether a particular individual will develop breast cancer, ovarian cancer, both types of cancer, or neither cancer appears to vary considerably depending upon two factors: the precise type of mutation inherited and the locations of these mutations in the DNA sequences of the genes .
We’ve known about the roles of BRCA1 and BRCA2 in inherited breast and ovarian cancer for some time. The tumor suppressor genes, which code for proteins involved in DNA repair, were first isolated 20 years ago. However, over the years, we’ve also learned that each of these genes can contain different types of inherited mutations that vary among the individuals/families being studied. Until we understand with far greater precision how each of these many mutations (or even groups of mutations) affects individual cancer susceptibility, the best that health-care professionals can do is to offer BRCA1/2 carriers prevention guidance based on general risk calculations.
The new work by Penn’s Timothy Rebbeck, Katherine Nathanson, and their colleagues represents a significant step toward more precise and individualized risk calculations. In their study, the researchers teamed up with the Consortium of Investigators of Modifiers of BRCA (CIMBA), a collaboration that spans 33 nations on six continents. CIMBA’s database contains vast troves of genetic and health data on BRCA1/2 carriers from a wide range of races and ethnicities.
Of 19,591 women in the CIMBA database with BRCA1 mutations, 46 percent were diagnosed with breast cancer, 12 percent with ovarian cancer, and 5 percent with both cancers by the age of 70. It’s important to note that 37 percent of women with BRCA1 mutations had not developed cancer by the age of 70. The picture was similar for the 11,900 women with BRCA2 mutations: 52 percent were diagnosed with breast cancer, 6 percent with ovarian cancer, and 2 percent with both cancers by the age of 70. About 40 percent had not developed cancer by the age of 70.
To gather information that may help to refine the timing of prevention strategies, the Penn team also looked closely the age at which BRCA1 and BRCA2 carriers were diagnosed with cancer. For BRCA1, the average age at diagnosis for breast cancer was 39.9 and 50 for ovarian cancer, while for BRCA2, the average age for breast cancer diagnosis was 42.8 and 54.5 for ovarian cancer.
Then, the researchers went on to identify BRCA1/2 mutations associated with significantly different risks of breast and ovarian cancer. For example, mutations located near the ends of BRCA1 were associated with a greater risk for breast cancer, while mutations located near the middle—specifically, in a long protein-coding sequence called exon 11—appeared to confer a higher risk of ovarian cancer. Interestingly, mutations located in or near BRCA1’s exon 11 also tended to be associated with earlier onset of both types of cancer than mutations elsewhere in the gene.
While the new findings represents encouraging progress towards more precise prevention of cancer among BRCA1/2 carriers, researchers caution that much follow-up work is needed before such information can be used to guide the very difficult decisions currently faced by such women. Ultimately, our hope is not only to spare women with BRCA1/2 who are at low risk of cancer from needless surgery, but to use this newfound knowledge to develop drugs and other less-invasive strategies for cancer prevention in high-risk women.
Developing more individualized ways to prevent inherited cancer is just one of many things we at NIH are doing to realize the full promise of precision medicine. Check out the Precision Medicine Initiative to learn more about the research needed to move such innovation into virtually all areas of health and disease.
 BRCA1 and BRCA2: Cancer Risk and Genetic Testing (National Cancer Institute/NIH)
 Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. Rebbeck TR, Mitra N, Wan F, Sinilnikova OM, Healey S, McGuffog L, Mazoyer S, Chenevix Trench G, Easton DF, Antoniou AC, Nathanson KL, CIMBA Consortium. JAMA 2015;313(13):1347-1361.
Basser Research Center for BRCA, University of Pennsylvania, Philadelphia
Decision Tool for Women with BRCA Mutations, Stanford University, Palo Alto, CA
Timothy Rebbeck, University of Pennsylvania, Philadelphia
Katherine Nathanson, University of Pennsylvania, Philadelphia
The Consortium of Investigators of Modifiers of BRCA1/2, University of Cambridge, England
NIH Support: National Cancer Institute