Tracing Breast Cancer’s History

In today’s New York Times, the actress Angelina Jolie published a remarkably forthcoming op-ed about getting a double mastectomy. Jolie carries a variant of a gene called BRCA1 that makes women highly likely to develop breast and ovarian cancer. Her mother, who also carried the variant, died of ovarian cancer at age 56. Like a number of other women with her condition, Jolie decided to get a mastectomy as a preventative measure.

A number of studies have shown that bilateral risk-reducing mastectomies (the official term) do indeed reduce the risk of breast cancer in women with the BRCA1 mutation. In a study published last month in Annals of Oncology, a team of Dutch medical researchers tracked 570 women with BRCA1 (or a mutation in the related gene BRCA2). At the start of the study, all the women were healthy; 212 of them later chose to get risk-reducing mastectomies. Over the next few years, the researchers followed their progress. Sixteen percent of the women who didn’t get risk-reducing mastectomies developed breast cancer; of the women who went Jolie’s route, none did.

The initials in BRCA1 stand for breast cancer. Its name reflects how it was discovered: scientists found it as they were searching for the cause of the disease. But such names are really misnomers. After all, genes don’t simply sit in our DNA so that they can mutate in some people and make them sick. Normally, they have a job to do. In the case of BRCA1, there are many jobs. For one thing, it protects DNA from harmful mutations that can arise as it’s getting replicated. And if DNA does get damaged, the BRCA1 protein helps fix it. It joins together with several teams of other proteins, and each team carries out a different part of the complex task of DNA repair.

BRCA1, in other words, normally keeps our cells in good shape. If it mutates, though, it can’t do its jobs properly. Cells with a mutant copy of BRCA1 let mistakes slip by. Mutations in other genes can accumulate in a line of dividing cells. Some of those mutations will cause cells to die, but sometimes they have the opposite effect: the mutant cells grow and divide rapidly. As they proliferate, they accumulate even more mutations, eventually becoming full-blown cancer. As a result, women who carry BRCA mutations have a 40 to 85 percent risk of developing breast cancer during their lifetime. (They also run a 16 to 64 percent risk of ovarian cancer.)

Last year, a team of scientists at the University of Utah discovered an unexpected side effect of BRCA mutations. They looked at medical records of women who carried BRCA mutations and compared them to women with a normal version of the genes. The scientists found that women with the mutations weren’t just more likely to develop cancer. They also had more children. The effect was particularly strong among women born before 1930: they had, on average, two additional children (6.22 compared to 4.19).

The Utah scientists couldn’t say from their study how the mutations could lead to more children. But they offered one suggestion. A woman’s fertility depends on the viability of her eggs. Like other cells, eggs have caps called telomeres on the ends of their chromosomes that keep them from getting damaged. The longer the telomeres, the better shape an egg is in. Among its many jobs, BRCA1 helps control the length of telomeres. The Utah scientists suggest that mutant BRCA1 proteins may lengthen the telomeres in eggs, keeping them more viable.

BRCA mutations are so good for fertility that Jack da Silva, a biologist at the University of Adelaide,  has pointed out that they should be a lot more common. Only a few percent of women carry them, but they enable women to have so many more children, you’d expect the mutation to become more common with each generation. Within a few centuries of the mutation first appearing, everyone should have it.

Da Silva proposes that the mutations hang in an evolutionary balance. Before the age of 40, a woman with a BRCA mutation only has a 20% chance of developing breast cancer. That risk rises to 37 percent by the age of 50 and continues going up; by the age of 70, it’s 70 percent. In other words, these women have good odds of surviving to the point at which they can give birth to children, but they’re less likely to be alive to see their own children become parents.

A number of biologists have argued that grandmothers have played an important part in the survival of their grandchildren. In fact, some maintain that their help is so valuable that menopause evolved as a result. Women who stop raising their own children can better channel their efforts into helping to raise their grandchildren. Women with BRCA mutations are less likely to be able to provide that help. As a result, Da Silva suggests, the odds of their grandchildren surviving may have been somewhat lower than for grandmothers without the mutations.

This balance could account for the puzzling nature of BRCA mutations. They’re more common than other potentially fatal disorders like cystic fibrosis, and they’re unable to spread to more than a few percent of the population. It is this ancient legacy of BRCA’s many effects that women like Jolie are grappling with today.

[Update 5/14: I corrected the cause of Angelina Jolie’s mother’s death from breast to ovarian cancer.]