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What is a BRCA Mutation?

Dr. Rebecca Arend University of Alabama-Birmingham

What is a BRCA mutation? BRCA (a breast cancer gene mutation) is actually two genes (BRCA1 and BRCA2), each proteins that work as tumor suppressors. They help repair damaged DNA, and are important for ensuring the stability of each cell’s genetic material.

When either of these genes is altered, that mutation can mean that its protein product does not function properly, or that damaged DNA may not be repaired correctly. These inherited mutations in BRCA1 and BRCA2 can increase the risk of female breast and ovarian cancers, and have also been associated with increased risks for several other cancers. Dr. Rebecca Arend, Associate Scientist at the University of Alabama, Birmingham, explains the mutation in terms of its ability to repair damaged DNA: “What a BRCA mutation is, is a defect in your ability to repair a double-strand break (in your DNA).” The BRCA mutation (which is passed on from a father or a mother), can cause a variety of cancers, including fallopian tube and peritoneal cancer, which are ovarian cancers. Furthermore, while about 1.3 percent of women in the general population will develop ovarian cancer sometime during their lives, it is estimated that about 44 percent of women who inherit a harmful BRCA1 mutation, and about 17 percent of women who inherit a harmful BRCA2 mutation, will develop ovarian cancer.”

There are several different genetic tests available to find out if you have the BRCA1 or BRCA2 gene mutation. If you discover that you do have a mutation, there are options available to manage your cancer risk, which include enhanced screenings; prophylactic (risk-reducing) surgery, which involves removing as much of the “at-risk” tissue as possible; and chemoprevention, the use of medicines to reduce the risk of cancer. Ironically, if you do discover you have ovarian cancer, it actually can be advantageous to have a BRCA mutation, as long as you are being treated with a PARP inhibitor, a drug therapy that was developed and approved by the FDA beginning in 2014. PARP inhibitors work by blocking the protein PARP from repairing the damaged DNA that can lead to cancer. These inhibitors kill the dangerous cells but leave the healthy ones intact, which is, of course, exactly what you want to happen.

“You think about DNA being a double helix, which we all learned about in basic science,” says Dr. Arend. “If you have a single-strand break, a PARP enzyme is needed to repair that single-strand break. If you have a PARP inhibitor, then you can’t repair that single-strand break. If you have a single-strand break that’s not repaired, that actually leads to a double-strand break.”

DNA is constantly breaking down in the body, and when both of the arms of the DNA helix are broken, your  body has a normal mechanism to fix that, known as Homologous Recombination. This is the body’s natural way of repairing harmful breaks on both strands of the DNA and is hugely important in maintaining genetic information in the body. If you have a BRCA mutation, however, your body won’t be able to repair the break, a term in medicine called Synthetic Lethality. Dr. Arend notes, “The PARP inhibitor prevents the repair of the (damaged) single-strand DNA break, and your BRCA mutation prevents the  repair of the double-strand DNA break.”

DNA double-strand breaks are traditionally associated with cancer, because they cause chromosome instability or gene mutation. The bottom line: If these DNA breaks happen to damaged DNA, this is all good news for your body. The cancer cells then have nothing left to do but disintegrate. As Dr. Arend explains, “it’s a perfect storm and the [cancerous cells] die.”

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Dr. Rebecca Arend is an Associate Scientist at the University of Alabama-Birmingham (UAB) Comprehensive Cancer Center Experimental Therapeutics Program. Read More

Ovarian Cancer: Screening and Risk

Ovarian cancer is notoriously hard to detect in the early stages when it’s most effectively treated. That’s why women should evaluate their risk factors for the disease and be vigilant about possible symptoms and warning signs.