BRCA2

Homologous recombinational repair of DNA double-strand damage

BRCA1 and BRCA2 mutations and absolute cancer risk

BRCA2 (Breast Cancer Type 2 susceptibility protein) is a protein that in humans is encoded by the BRCA2 gene. BRCA2 is involved in the repair of DNA damage and plays a critical role in maintaining the genetic stability of cells. When this gene is mutated, it significantly increases the risk of developing certain cancers, most notably breast cancer and ovarian cancer. The discovery of the BRCA2 gene has had a profound impact on the understanding and management of hereditary cancers.

Function

The BRCA2 protein is essential for the repair of DNA double-strand breaks through the homologous recombination repair pathway. It acts by binding to and regulating the activity of RAD51, a recombinase involved in the homologous recombination process. By doing so, BRCA2 facilitates the accurate repair of DNA breaks, thereby preventing mutations that could lead to cancer.

Genetics

The BRCA2 gene is located on the long (q) arm of chromosome 13 at position 13.1, specifically at 13q13.1. Mutations in this gene are inherited in an autosomal dominant manner, meaning a mutation in one of the two copies of the gene is sufficient to increase an individual's cancer risk. There are hundreds of different mutations in the BRCA2 gene that can increase the risk of cancer, ranging from small deletions or insertions to large genomic rearrangements.

Cancer Risk

Individuals with mutations in the BRCA2 gene have a significantly increased risk of developing breast and ovarian cancers. Women with harmful BRCA2 mutations have about a 45-65% risk of developing breast cancer by age 70. The risk for ovarian cancer is also increased, though to a lesser extent than with BRCA1 mutations. Men with BRCA2 mutations also have an increased risk of breast cancer, though it is much lower than in women, and they have an increased risk of developing prostate cancer. Additionally, BRCA2 mutations can increase the risk of other cancers, such as pancreatic cancer and melanoma.

Testing and Management

Genetic testing for BRCA2 mutations is available and is often recommended for individuals with a strong family history of breast or ovarian cancer. Identifying a BRCA2 mutation can inform cancer screening and prevention strategies. Options for managing increased cancer risk may include increased surveillance, prophylactic surgery (such as mastectomy and oophorectomy), and chemoprevention.

Ethical and Social Considerations

The identification of BRCA2 mutations raises important ethical and social considerations, including issues of privacy, discrimination, and the psychological impact of genetic risk information. It is crucial that individuals undergoing genetic testing for BRCA2 mutations receive appropriate genetic counseling to understand the implications of test results.

Research Directions

Research on BRCA2 continues to evolve, with studies focusing on understanding the detailed mechanisms of its action in DNA repair, the development of targeted therapies for cancers associated with BRCA2 mutations, and the identification of factors that modify cancer risk in mutation carriers.