Researchers may have advanced the understanding of genetic alterations in the BRCA2 gene, according to a recent study published by Huang et al in Nature. The findings could improve the accuracy of genetic testing and allow health-care professionals to offer more precise risk assessments and personalized treatment plans for patients carrying variants of uncertain significance.
Study Methods and Results
In the multi-institutional, international study, researchers performed a comprehensive functional assessment of all possible variants within the crucial DNA-binding domain of BRCA2, resulting in the clinical classification of 91% of variants of uncertain significance in this part of the gene.
They utilized clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene-editing technology to analyze the functional impact of almost 7,000 BRCA2 variants, definitively identifying those that increase cancer risk and those that do not.
The new information could eliminate much of the uncertainty surrounding variants of uncertain significance, allowing for more informed decisions regarding cancer screening, preventive measures, and treatment strategies. The findings have immediate implications for genetic testing laboratories and health-care professionals, aiding them in offering more precise and personalized care to patients with variants of uncertain significance.
“This research is a major advancement in understanding the role of many BRCA2 variants in cancer predisposition,” highlighted senior study author Fergus Couch, PhD, the Zbigniew and Anna M. Scheller Professor of Medical Research at the Mayo Clinic. “Until now, patients who carried [variants of uncertain significance] often worried if they would develop cancer, but now, with the classification of these variants, we can provide a clearer picture of cancer risk and tailor both prevention strategies as well as breast cancer treatment accordingly,” he underscored.
Many patients with variants of uncertain significance may be notified about the reclassification of their variants as the ClinVar BRCA1/2 expert panel and testing laboratories use the new information in testing reports and updates. In addition, the new insights could aid in identifying patients with breast, ovarian, pancreatic, or prostate cancers who may benefit from targeted therapies such as poly-ADP ribose polymerase inhibitors.
“We now have a catalog of every possible [variant of uncertain significance] in this part of BRCA2 that can be used to guide clinical care,” Dr. Couch indicated.
The researchers noted that their research could lay the groundwork for future studies characterizing and classifying all BRCA2 variants across diverse populations and cancer types, thereby improving risk assessment for all patients.
Disclosure: The research in this study was funded by the National Cancer Institute, Mayo Clinic Breast Cancer SPORE and R35 Outstanding Investigator Programs, the Mayo Clinic Comprehensive Cancer Center, and the Breast Cancer Research Foundation. For full disclosures of the study authors, visit nature.com.
