Fergus J. Couch, PhD

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 germline (inherited) DNA from 32,247 women with breast cancer and 32,544 unaffected women. They sought 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, African American, and Hispanic women. Not surprisingly, the highest frequency of mutations was observed in BRCA1 and BRCA2. Mutations in PALB2 were also correlated with moderate risk.

The researchers also correlated specific gene mutations with subtypes of breast cancer. Mutations on the BARD1, RAD51C, and RAD51D genes, while very uncommon, were associated with an increased risk of ER-negative and triple-negative breast cancer and were more frequent in African American women with breast cancer. 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—providing new insight into the racial difference in frequency of ER-negative versus ER-positive breast cancers.

What’s next

There are other types of mutations called “variants of uncertain significance (VUS)” that are identified by cancer genetic screening. However, they complicate the results because, as their designation implies, their role in cancer development is uncertain. As a result, those with VUS cannot benefit from improved clinical management in the same way as those with BRCA1/2 mutations. For instance, a finding of VUS does not qualify an individual for enhanced cancer screening with mammograms and MRI. And currently there are no targeted treatments for breast cancers with these mutations unlike those with pathogenic BRCA1/2 variants. There are over 4,000 VUS reported in BRCA2. Dr. Couch is building on prior studies that evaluated 450 BRCA2 VUS. They will now use a cutting-edge tool–CRISPR/cas9 targeting—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.