Fergus J. Couch, MD

Identifying genes beyond the well-known BRCA1 and BRCA2 genes that increase the risk of breast cancer to improve breast cancer risk prediction in women at high-risk.

Impact

Inherited breast cancer risk is most commonly associated with mutations in the BRCA1 and, to a lesser extent, BRCA2 genes. However, these are not the only established breast cancer susceptibility genes. Between seven and 10 percent of women with breast cancer are estimated to have mutations in breast cancer predisposition genes. But these estimates were based on studies of limited size and in high-risk populations. With early and sustained BCRF support, Dr. Couch and his colleagues undertook the CARRIERS (Cancer Risk Estimates Related to Susceptibility) study to examine genetic risk that could be applied to the general population, including African American, Asian, and Hispanic women. In this study, the team analyzed DNA from 32,247 women with breast cancer and 32,544 unaffected women seeking to answer two key questions: How frequently do mutations occur among genes, and can these gene mutations provide an accurate estimate of one’s risk of developing breast cancer? This is the first comprehensive study to examine the prevalence of inherited mutations in established breast cancer susceptibility genes. The insights gained from these studies will lead to more informed, accurate, and beneficial risk management and guide therapy decisions for many women at increased risk of breast cancer.

Progress Thus Far

Dr. Couch and his colleagues evaluated the frequency of mutations in 12 established predisposition genes, including BRCA1, BRCA2, PALB2, BARD1, and ATM. Mutations were detected in five percent of women with breast cancer, compared to 1.6 percent of unaffected women. Similar frequencies were observed among non-Hispanic white, Black , and Hispanic women. Not surprisingly, the highest frequency of mutations was observed in BRCA1 and BRCA2. Mutations in ATM, CDH1, and CHEK2 were linked to an increased risk of ER-positive breast cancer and more frequent in non-Hispanic white women, while mutations in BARD1, RAD51C, and RAD51D were associated with ER-negative and triple-negative breast cancer and more frequent in Black women. In the past year, the team used functional studies to resolve the clinical relevance of nearly 3,000 different alterations in the PALB2, ATM, and RAD51D genes. They also identified 250 variants in BRCA2 that only partially affect gene function—called hypomorphic variants—which appear to confer a lifetime breast cancer risk of roughly 20–25 percent rather than the 70 percent associated with fully pathogenic variants, meaning individuals who carry them will require a very different approach to risk management.

What’s next

Dr. Couch’s team is utilizing CRISPR/cas9 gene editing technology to evaluate possible variants in the key functional parts of BRCA2 at the same time. The team can leverage this strategy to examine the effects of more than 7,000 possible variants in BRCA2, determine the clinical relevance of these variants, and ultimately make the information available to improve breast cancer care for anyone found to carry one of these variants.