BRCA1 and BRCA2: Understanding Hereditary Breast and Ovarian Cancer Genes

The BRCA1 and BRCA2 genes are among the most studied in all of human genetics. Mutations in these genes substantially increase the risk of breast and ovarian cancer, and understanding their biology has transformed cancer risk assessment, prevention, and treatment.

BRCA1 and BRCA2: Their Normal Functions

BRCA1 and BRCA2 are tumor suppressor genes—they normally function to prevent cancer by maintaining genome integrity. Both proteins play critical roles in DNA double-strand break repair through homologous recombination (HR), a high-fidelity repair pathway. BRCA1 acts early in the HR process, facilitating end resection and BRCA2 recruitment. BRCA2 directly loads RAD51 onto single-stranded DNA, enabling strand invasion and accurate repair.

When one copy of BRCA1 or BRCA2 is mutated in the germline (inherited from a parent), a person is a carrier. If the remaining functional copy is lost in a cell (the second hit), that cell can no longer perform high-fidelity DNA repair, leading to genomic instability and cancer development.

Cancer Risk Associated with BRCA Mutations

The lifetime cancer risks for pathogenic BRCA1 mutation carriers include breast cancer risk of approximately 60-70% (compared to 12% population risk), ovarian cancer risk of approximately 40-45% (compared to 1.3% population risk), and additional increased risks for pancreatic cancer, prostate cancer, and other malignancies. BRCA2 carriers face breast cancer risk of approximately 50-60%, ovarian cancer risk of 15-25%, and significantly elevated pancreatic cancer and male breast cancer risk.

BRCA Testing: Who Should Be Tested?

Genetic testing for BRCA1/2 mutations is recommended for individuals with a personal or family history suggestive of hereditary breast-ovarian cancer syndrome: multiple family members with breast or ovarian cancer; cancer at young age; bilateral breast cancer; male breast cancer; Ashkenazi Jewish ancestry (higher BRCA mutation carrier frequency); triple-negative breast cancer; and ovarian, fallopian tube, or primary peritoneal cancer.

Management Strategies for BRCA Carriers

Options for BRCA mutation carriers include enhanced screening (annual MRI and mammography starting at age 25-30 for BRCA1; 30-35 for BRCA2), risk-reducing surgery (bilateral mastectomy reduces breast cancer risk by ~95%; bilateral salpingo-oophorectomy reduces ovarian cancer risk and may also reduce breast cancer risk), and chemoprevention. PARP inhibitors (olaparib, niraparib, rucaparib) specifically exploit the HR deficiency in BRCA-mutant tumors, providing targeted treatment options for BRCA-associated cancers.

For more on hereditary cancer genetics, visit our research blog.