Findings from an international, multi-institutional study have significantly improved our knowledge of genetic changes in the BRCA2 gene, which plays a critical role in hereditary cancer risk.
A collaborative study spearheaded by researchers at the Mayo Clinic Comprehensive Cancer Center has made significant strides in understanding the genetic alterations in the BRCA2 gene, vital for hereditary cancer risk. Through a thorough investigation of all possible variants within the essential DNA-binding region of BRCA2, the researchers successfully classified 91% of variants of uncertain significance (VUS) within this gene segment. This major achievement enhances the reliability of genetic testing and enables healthcare providers to offer more accurate risk evaluations and tailored treatment options for individuals with these variants.
The research, published in Nature, employed CRISPR-Cas9 gene-editing technology to examine the functional consequences of nearly 7,000 BRCA2 variants, clearly identifying which ones pose an increased cancer risk and which do not. This new knowledge will alleviate much of the confusion surrounding VUS, facilitating better-informed choices about cancer screenings, preventive actions, and treatment plans.
“This study represents a significant leap in our understanding of how numerous BRCA2 variants contribute to cancer risk,” remarks Fergus Couch, Ph.D., the Zbigniew and Anna M. Scheller Professor of Medical Research at Mayo Clinic. “Previously, patients with VUS often had concerns about their cancer risk, but now, with these variants clearly classified, we can offer a more accurate assessment of cancer risk and customize both preventive actions and breast cancer therapies accordingly.”
The implications of these findings are immediate for genetic testing laboratories and healthcare professionals, helping them deliver more precise and individualized care to patients with VUS. Many individuals with VUS might soon be informed about the reclassification of their variants as the ClinVar BRCA1/2 expert panel and testing facilities incorporate this new data into their testing reports and updates. Furthermore, this understanding will assist in identifying patients with breast, ovarian, pancreatic, or prostate cancer who could benefit from targeted treatments such as PARP inhibitors.
“We now possess a comprehensive catalog of every VUS in this segment of BRCA2, which can inform clinical care,” states Dr. Couch.
The researchers believe that this study establishes a foundation for future investigations to characterize and classify all BRCA2 variants across different populations and types of cancer, enhancing risk assessments for everyone involved.
The collaborative effort included contributors from Ambry Genetics Inc., Duke University, H. Lee Moffitt Cancer Center, the University of Pennsylvania, and additional studies from the CARRIERS consortium. Funding for the study was provided by the National Cancer Institute, the Mayo Clinic Breast Cancer SPORE (P50 CA116201), the R35 Outstanding Investigator Programs, the Mayo Clinic Comprehensive Cancer Center, and the Breast Cancer Research Foundation.
