A large systematic analysis of BRCA1 and BRCA2 mutations in women shows that mutation location and type is associated with significant variation in the risk for breast and ovarian cancers.
Pathogenic mutations in the tumor suppressor genes BRCA1 or BRCA2 increase the lifetime risk of breast cancer and ovarian cancer, and are associated with an earlier occurrence of cancer. Genetic screening has identified dozens of different deleterious mutations, but the risks associated with any given mutation have been largely unknown.
Now, a large systematic analysis of BRCA1 and BRCA2 mutations in women shows that mutation location and type is associated with significant variation in the risk for breast and ovarian cancers.
In the new study, investigators retrospectively tallied cancer occurrence in a large group of 31,481 women positive for BRCA1 or BRCA2 mutations, drawn from 55 centers in 33 countries as part of the Consortium of Investigators of Modifiers of BRCA research initiative. In all, 63% of BRCA1 mutation carriers and 60% of BRCA2 carriers in the study were diagnosed with breast or ovarian cancer, or both, allowing calculation of hazard ratios for both cancers by mutation type and location.
The results identify clusters of breast or ovarian cancer–related mutations in each gene, as well as some mutations associated with earlier age of cancer diagnosis.
The findings will allow more precise, personalized risk assessment for women with BRCA1 or BRCA2 mutations, says Timothy R. Rebbeck, PhD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and lead author on the study published in the Journal of the American Medical Association.
Current predictions rely on blanket estimates derived from the whole population, which may be inaccurate for individual women. “This work shows that the mutation inherited actually confers a very specific risk; some women may have a lower risk, some much higher,” Rebbeck says.
It remains to be seen how the new information will affect women's perception of their risk, or their behavior. For example, BRCA1 mutations in general confer a 59% risk of breast cancer before age 70. For women with a specific class of mutations, the risk increases to 69%. “In some ways that seems like a lot, but we don't know what these numbers mean to a woman when she is being counseled,” Rebbeck says. “We don't know how much this will change people's perception of their risk and what they do about it. That's research that needs to be done next.”
The results may also lead to new insights about the biologic roles of BRCA genes in breast and ovarian carcinogenesis. By implicating different regions of the protein in the different cancers, the results raise hypotheses that can be further tested in animal models, Rebbeck says.