Cracking The Code: Understanding the Function of BRCA Genes

By Dr. Kathleen T. Ruddy

Angelina Jolie shocked the world last week with her announcement that she had inherited a BRCA 1 mutation – presumably from her mother who died of ovarian cancer in her 50′s – and had elected to have her breasts removed in the hope of increasing her chances of living long enough to raise her six children.  The fact that any woman, especially an exquisitely beautiful star like Jolie, should have to mutilate herself to prolong her life brought the world up short and breathless and looking for answers.  After the trauma of the news wore off, many women wanted to understand more about these BRCA genes, what they do, what they fail to do when they are mutated, and why women have so few choices in dealing with a genetic deck stacked against them.

So, what are these BRCA genes and what function do they provide in normal women?  BRCA genes serve to protect the cell from DNA damage.  The BRCA genes are involved in repairing DNA altered by carcinogens or mishaps that are part of the everyday life of the cell.  If one of these BRCA genes – BRCA 1, found on chromosome 17, or BRCA 2, found on chromosome 13 – becomes mutated the cell can no longer defend itself as well and is at an increased risk for malignant transformation.

BRCA mutations occur in both men and women.  When a BRCA mutation does occur, it can be passed down from mother or father to the children.  Boys that inherit a BRCA mutation can live long and healthy lives (though they are at an increased risk for prostate cancer) and can, in turn, pass the mutated gene to their daughters who are then at a significantly increased risk for breast and ovarian cancer.  Mothers who carry a BRCA mutation can pass it on to their children – to their sons who pass it on to their children, and to the daughters who pass it on but are also at an increased risk for breast and ovarian cancer.

Other cancers are associated with a BRCA mutation: pancreatic and colon.  The overall risk for all of these BRCA mutation-associated tumors covers a wide spectrum.  That’s because there are many mutations that have been identified in these two BRCA genes, and each mutation is associated with its own specific risk for each kind tumor (breast, ovary, pancreatic, colon, and prostate.)

In addition, other known and proven breast cancer risk factors, such as use of oral contraceptives, smoking, and alcohol ingestion, can interact with the mutated BRCA gene and increase the risk for malignancy even further.

In the case of Angelina Jolie, she was identified as a BRCA 1 mutation carrier because her mother died of ovarian cancer.  Any woman with a close family relative who has been diagnosed with ovarian cancer is a good candidate for BRCA testing because ovarian cancer is so often associated with a mutation in a BRCA gene.  When tested, Jolie was found to carry a BRCA 1 mutation; though, statistically, she had only a 50% chance of inheriting this mutated gene from her mother.  In any case, she did inherit a BRCA 1 mutation and, thus, she is at a significantly increased risk for breast and ovarian cancer (and an increased risk for pancreatic and colon cancer.)

Jolie has another risk factor that strongly impacts her already elevated risk:  she has three biologic children.  For women who carry a BRCA mutation, each pregnancy further increases the high baseline risk for breast cancer.  So whereas scientists might say that, on average, a BRCA 1 mutation carrier may have a 50% risk of developing breast cancer by age 50 (the risk increases every year as a woman gets older), Jolie told us that her lifetime risk for developing breast cancer was 87%.  That makes sense given her BRCA 1 mutation and her history of bearing three children.

Jolie’s choice to have her breasts removed reduces her risk for breast cancer approximately 90%.  It does not reduce the risk completely because even during the most thorough mastectomy, some residual BRCA-mutated cells are left behind that retain the potential for malignant transformation.  Unfortunately, Jolie can still get breast cancer, but now she has only a 10% chance – which is higher than the average American risk (currently 7%).

If Jolie had only her ovaries removed before she turned 40, she would reduce her risk for breast cancer by 50% and reduce her risk for ovarian cancer by 85%.  Removing the ovaries lowers the risk for breast cancer because the hormones made by the ovaries, estrogen and progesterone, play a strong role in all breast cancer formation.

For BRCA mutation carriers, the single best intervention to lower the risk for breast and ovarian cancer is to remove the breasts by age 25 and the ovaries by age 40.  Such an aggressive, albeit mutilating, intervention can lower the risk of death from these diseases to nearly the level seen in the unaffected population; that is, women who do not carry a BRCA mutation.

An alternative to prophylactic mastectomy, and one that makes sense for many women, is to have the ovaries removed by age 40 (which, as I say, cuts the risk for breast cancer in half) and to undergo an aggressive breast cancer screening program, with an annual mammogram and breast MRI, each staggered so that one screening method is performed every six months.  This recipe yields approximately 95% of the survival benefit achieved by surgically removing the breasts.

Like the rest of us, Jolie’s genes were thrust upon her by chance.  The dilemma she faced was difficult, and her choices limited and unpleasant to say the least.  She has done what she thought best for herself and her children.   She has been very brave.  She deserves our deepest compassion and support.  While we send her our very best wishes for a speedy recovery and a long life, we look forward to the day when we crack the code, can dig down on those aberrant genes and make them behave.  Until then, we open our hearts and arms to courageous women like Jolie who are forced to live under the sword of a BRCA mutation and the knife of prevention.