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About BRCA and Related Genes

  • Doctors Alan D'Andrea, Judy Garber, and Eric Winer

  • BRCA1 and BRCA2 occupy a central role in the repair of a specific type of damage to the DNA through a DNA repair pathway called homologous recombination repair (HRR). Multiple other genes (referred to as BRCA-related genes) also participate directly or indirectly in HRR. These genes include PALB2, BARD1, BRIP1, RAD50, RAD51C, RAD51D, RAD54L, ATM, ATR, ATRX, FANCONI anemia genes (e.g. FANCA, FANCB, FANCC), CHEK1, CHEK2, BLM, NBN, MRE11A, and others.

    BRCA1, BRCA2 and BRCA-related genes are frequently mutated in multiple tumor types, especially breast, ovarian, pancreatic, and prostate cancers, and other malignancies. Mutations in these genes may be present in the germline (i.e., hereditary and detectable via genetic testing) or may be present in the tumor only, i.e., detected via testing of the tumor using institutional (such as Dana-Farber's Oncopanel), commercially available assays examining tumor DNA, or liquid biopsies, such as from Foundation Medicine or Gardant.

    Approximately 10-15% of patients with ovarian, breast, pancreatic, and prostate cancers have germline (heritable) BRCA1/2 mutations, and another 15-30% of patients have somatic BRCA1/2 mutations or somatic alterations in BRCA-related genes. Tumors with mutations in BRCA and BRCA-related genes are particularly sensitive to treatments that cause damage to the DNA, such as platinum-based chemotherapy and targeted agents such as PARP inhibitors. Of note, PARP inhibitors induce a type of DNA damage that cannot be repaired in tumors with mutations in BRCA and BRCA-related genes, and are therefore particularly active against these tumors. PARP inhibitors are now FDA-approved for ovarian, breast, pancreatic, and prostate cancers and represent the first DNA repair targeted therapy approved for cancer patients.

    Glossary

    Mutation: A change in the usual DNA sequence at a segment of a gene. Mutations can be harmful, beneficial, or neutral in their effect on cell function.

    Germline mutation: A gene change in a body's reproductive cell (egg or sperm) that becomes incorporated into the DNA of every cell in the body of the offspring. Germline mutations are passed on from parents to offspring. Also called hereditary mutation.

    Somatic mutation: An alteration in DNA that occurs after conception. Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children. These alterations can (but do not always) cause cancer or other diseases. Most mutations in cancer are somatic mutations.

    DNA repair: The process of restoring DNA after damage. DNA is subject to damage by chemical and physical agents in the environment (e.g. UV and ionizing radiations, chemical mutagens, fungal and bacterial toxins, etc.).

    DNA repair genes: DNA repair genes encode enzymes which fix DNA damage. Such genes include PALB2, BARD1, BRIP1, RAD50, RAD51C, RAD51D, RAD54L, ATM, ATR, ATRX, FANCONI anemia genes (e.g. FANCA, FANCB, FANCC), CHEK1, CHEK2, BLM, NBN, MRE11A, and others.

    Oncopanel: Oncopanel is Dana-Farber's advanced next-generation sequencing platform that can detect not only genetic mutations, but also other critical types of cancer-related DNA alterations, such as copy number variations and structural variations.

    Targeted therapy: A type of treatment that uses drugs or other substances to identify and attack specific types of cancer cells with less harm to normal cells. Some targeted therapies block the action of certain enzymes, proteins, or other molecules involved in the growth and spread of cancer cells. Other types of targeted therapies help the immune system kill cancer cells or deliver toxic substances directly to cancer cells and kill them. Targeted therapy may have fewer side effects than other types of cancer treatment. Most targeted therapies are either small molecule drugs or monoclonal antibodies.

    PARP inhibitors: PARPs (or Poly (ADP-ribose) polymerases) are proteins that play an important role in the life of a cell. When a single strand of the DNA double helix is broken or damaged, PARPs act as a repair crew to help fix the damaged site, allowing the cell to live. When BRCA1 or BRCA2 is not functioning well, cancer cells depend on PARPs to remain alive, grow, and divide. Therefore, drugs that inhibit or stop PARPs from doing their job (PARP inhibitors) can kill cancer cells, especially those with BRCA1 or BRCA2 mutations.

    microRNA: A type of RNA found in cells and in blood. MicroRNAs are smaller than many other types of RNA and can bind to messenger RNAs (mRNAs) to block them from making proteins. MicroRNAs are being studied in the diagnosis and treatment of cancer. Also called miRNA.

    RANKL inhibitor: Receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitors are used to treat osteoporosis, breast cancer, lung cancer, and prostate cancer. They work by preventing bone fractures and by destroying cancer cells. Their main target is a type of bone cells called osteoclasts, which are cells that break down bone.

    Immunotherapy: Immunotherapy is a type of therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection, and other diseases. Some types of immunotherapy only target certain cells of the immune system. Others affect the immune system in a general way.