Fergus J. Couch, PhD
Professor of Laboratory Medicine And Pathology
Zbigniew and Anna M. Scheller Professor of Medical Research
Chair, Division of Experimental Pathology and Laboratory Medicine,
Department of Laboratory Medicine and Pathology
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.
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.
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.
Dr. Couch and his colleagues will continue to characterize breast cancer risk associated with variants in known cancer predisposition genes as well as the new candidate moderate-risk genes. In addition, they will continue their studies to determine which gene variants of uncertain significance contribute to breast cancer risk and correlate expression of specific variants with patient response to endocrine agents and chemotherapy.
Fergus Couch is Professor and Chair of the Division of Experimental Pathology and Laboratory Medicine at the Mayo Clinic, with joint appointments in the Departments of Health Sciences Research and Biochemistry and Molecular Biology. Dr. Couch works on the genetics of breast cancer, with over 300 publications relating to the discovery and clinical characterization of inherited genetic variants in cancer susceptibility genes. He is the principal investigator of the Mayo Clinic Breast Cancer Registry and is a founder and a member of the coordinating committee of CIMBA (the consortium of investigators of modifiers of BRCA1/2) focused on identifying genetic modifiers of breast cancer risk in the BRCA1 carrier population. Similarly, he is the principal investigator of the Triple Negative Breast Cancer Consortium (TNBCC), aimed at understanding the genetic etiology of triple negative breast cancer, and is a long-term contributor to the international Breast Cancer Association Consortium (BCAC). Dr. Couch is a co-founder of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium focused on establishing the clinical relevance of variants of uncertain significance (VUS) in BRCA1/2. Within ENIGMA he is coordinating efforts to characterize the risk and penetrance of deleterious mutations and VUS in non-BRCA1/2 predisposition genes. He has also collaborated with investigators from Memorial Sloan Kettering Cancer Center and the University of Pennsylvania to develop the Prospective Registry Of Multi-Plex Testing (PROMPT) for patients with mutations in predisposition genes. Dr. Couch is a founding member and participant in COMPLEXO, a consortium aiming to identify additional breast cancer predisposition genes.
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