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Researchers at Huntsman Cancer Institute (HCI) at the (U of U) contributed to the development of a global resource that includes data on thousands of inherited variants in the BRCA1 and BRCA2 genes. This resource, called the BRCA Exchange, is now available to the public. The BRCA Exchange was created through the BRCA Challenge, a long-term demonstration project initiated by the Global Alliance for Genomics and ÑÇÖÞ×ÔοÊÓƵ (GA4GH) to enhance sharing of BRCA1/BRCA2 data. The new resource will allow clinicians to review expert classifications of variants in these major cancer predisposition genes as part of their individual assessment of cancer prevention, screenings, and interventions for patients at higher risk for breast, ovarian, and certain other cancers.

, a cancer researcher at HCI and professor of oncological sciences at the U of U, and David Goldgar, PhD, also a cancer researcher at HCI and adjunct professor in the department of dermatology at the U of U, have been involved in research on these two genes since before they were actually discovered. They’ve also been involved in the evaluation of sequence variants observed in the genes since shortly after the genes’ discovery. Their contributions to the research added historical background, detailed knowledge on the genes’ structures, and knowledge on methods of variant classification to the BRCA Exchange.

"Dr. Goldgar and I have been excited to see discoveries we contributed to in the 1990s translated for the benefit of patients and their at-risk relatives," said Tavtigian. "Yet the problem of classifying sequence variants observed during clinical testing has proven difficult. Solutions to this problem will be accelerated by the world-wide data sharing effort the BRCA Exchange is going to enable, resulting in greater benefit to patients around the world."

The five-year BRCA Challenge project was funded in part by the National Cancer Institute (NCI), part of the National Institutes of ÑÇÖÞ×ÔοÊÓƵ, and through the . A paper detailing the development of the BRCA Exchange was published today by PLOS Genetics.

"This project has yielded a meta-analysis of BRCA1 and BRCA2 variants collected from multiple sources to understand how experts annotate specific mutations in the two genes," said Stephen J. Chanock, MD, director of NCI’s Division of Cancer Epidemiology and Genetics and lead author of the paper. "There’s an urgent need for sharing data in cancer predisposition research. The BRCA Exchange is proof-of-principle that large-scale collaboration and data sharing can be achieved and can provide the latest and best quality information to enable clinicians and individuals to improve care."

Certain inherited variants in these genes can increase the risk of breast, ovarian, and other cancers by varying degrees, whereas other variants are not associated with disease. Clinicians and patients need to know whether a given variant is likely to be disease-associated (pathogenic) and how likely a pathogenic variant is to cause cancer. Until now, the available data on the inherited variants in these genes was not aggregated in a comprehensive way.

The BRCA Exchange dataset comprises information from existing clinical databases—Breast Cancer Information Core, ClinVar, and the Leiden Open Variation Database (LOVD)—as well as population databases and data from clinicians, clinical laboratories, and researchers worldwide. It currently includes more than 20,000 unique BRCA1 and BRCA2 variants. More than 6,100 variants in the database have been classified by an expert panel called the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA). Approximately 3,700 of those 6,100 variants are known to cause disease. The BRCA Exchange is now pooling variants from data resources worldwide, which should lead to inclusion of rare variants that are very occasionally observed.

With a , the BRCA Exchange now provides information on these gene variants to clinicians, researchers, data scientists, patients, and patient advocates. It also serves as a demonstration project showing that this kind of comprehensive data sharing—requiring collaboration across hundreds of organizations, the establishment of an infrastructure to house the information, and the development of data-sharing protocols—is possible for other cancer predisposition genes and, indeed, for genes associated with other diseases.

Next steps for the project include collaboration with additional global data generators and data holders, continued technical development, and increased engagement with patients and patient advocates around the world.

The HCI portion of this research was supported by National Institutes of ÑÇÖÞ×ÔοÊÓƵ/National Cancer Institute including P30 CA042014 and the Huntsman Cancer Foundation.