Not All BRCA Mutations Equal

Findings from a large study of more than 31,000 women known to carry mutations in the BRCA1 or BRCA2 genes could affect risk assessment and decision making for preventing ovarian and breast cancers, according to the report, which was published recently in JAMA. An international team of researchers found that distinct gene cluster regions in both BRCA1 and BRCA2 genes are associated with significantly different risks of breast and ovarian cancer.

It already was known that women who have mutations in BRCA1 or BRCA2 (BRCA1/2) are at increased risk for breast and ovarian cancer, but little is known about how that risk varies by the type of mutation. The new study—which included 19,581 women with BRCA1 mutations and 11,900 with BRCA2 mutations—sought to evaluate whether the type or location of the mutation was tied to a variation in cancer risk.

In the BRCA1 group, 46 percent were diagnosed with breast cancer, 12 percent with ovarian cancer, and 5 percent with breast and ovarian cancer; 37 percent remained without cancer. In the BRCA2 group, 52 percent developed breast cancer, 6 percent had ovarian cancer, 2 percent had breast and ovarian cancer, and 40 percent did not develop cancer during the study period. The researchers determined that the risk for breast and ovarian cancer varied by type and location of the mutations. Specifically, the investigators identified three BRCA1 breast cancer cluster regions (BCCR) and an ovarian cancer cluster region (OCCR). In the case of BRCA1, they delineated three BCCRs and three OCCRs. The researchers found distinct risk profiles associated with each cluster. For example, the BRCA1 OCCR bounded by c.1380 and c.4062 within exon 11 was associated with a relative decrease in breast relative to ovarian cancer risk. Similarly, the BRCA2 OCCR bounded by c.3249 and c.5681 and containing c.5946delT was associated with statistically greater ovarian cancer risk relative to breast cancer risk.

"This study is the first step in defining differences in risk associated with location and type of BRCA1 and BRCA2 mutations,” the researchers wrote. “Pending additional mechanistic insights into the observed associations, knowledge of mutation-specific risks could provide important information for clinical risk assessment among BRCA1/2 mutation carriers, but further systematic studies will be required to determine the absolute cancer risks associated with different mutations.”

Lead study author Timothy R. Rebbeck, PhD, who is a professor of epidemiology and the associate director for Population Science at Penn Medicine's Abramson Cancer Center, said the new findings could prove useful as a foundation for future research. “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,” Rebbeck said in a prepared statement. "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."

Exactly how the new research could prove meaningful for women who carry these mutations remains to be seen. “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 Katherine L. Nathanson, MD, co-author of the study and associate professor of medicine and director of genetics in the Basser Research Center for BRCA at Penn's Abramson Cancer Center, in a prepared statement. “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.”