yet been fully categorized for breast cancer risk).
In the summer of 2008, I met a woman with a family history of breast cancer. Jane Sterling was a thirty-seven-year-old nurse from the North Shore of Massachusetts. The story of her family could have been plucked straight out of Mary-Claire King’s case files: a great-grandmother with breast cancer at an early age; a grandmother who had had a radical mastectomy for cancer at forty-five; a mother who had had bilateral breast cancer at sixty. Sterling had two daughters. She had known about BRCA1 testing for nearly a decade. When her first daughter was born, she had considered the test, but neglected to follow up. With the birth of the second daughter, and the diagnosis of breast cancer in a close friend, she came to terms with gene testing.
Sterling tested positive for a BRCA1 mutation. Two weeks later, she returned to the clinic armed with sheaves of papers scribbled with questions. What would she do with the knowledge of her diagnosis? Women with BRCA1 have an 80 percent lifetime risk of breast cancer. But the genetic test tells a woman nothing about when she might develop the cancer, nor the kind of cancer that she might have. Since the BRCA1 mutation has incomplete penetrance, a woman with the mutation might develop inoperable, aggressive, therapy-resistant breast cancer at age thirty. She might develop a therapy-sensitive variant at age fifty, or a smoldering, indolent variant at age seventy-five. Or she might not develop cancer at all.
When should she tell her daughters about the diagnosis? “Some of these women [with BRCA1 mutations] hate their mothers,” one writer, who tested positive herself, wrote (the hatred of mothers, alone, illuminates the chronic misunderstanding of genetics, and its debilitating effects on the human psyche; the mutant BRCA1 gene is as likely to be inherited from a mother as it is from a father). Would Sterling inform her sisters? Her aunts? Her second cousins?
The uncertainties about outcome were compounded by uncertainties about the choices of therapy. Sterling could choose to do nothing—to watch and wait. She could choose to have bilateral mastectomies and/or ovary removal to sharply diminish her risk of breast and ovarian cancer—“cutting off her breasts to spite her genes,” as one woman with a BRCA1 mutation described it. She could seek intensive screening with mammograms, self-examination, and MRIs to detect early breast cancer. Or she could choose to take a hormonal medicine, such as tamoxifen, which would decrease the risk of some, but not all, breast cancer.
Part of the reason for this vast variation in outcome reflects the fundamental biology of BRCA1. The gene encodes a protein that plays a critical role in the repair of damaged DNA. For a cell, a broken DNA strand is a catastrophe in the making. It signals the loss of information—a crisis. Soon after DNA damage, the BRCA1 protein is recruited to the broken edges to repair the gap. In patients with the normal gene, the protein launches a chain reaction, recruiting dozens of proteins to the knife edge of the broken gene to swiftly plug the breach. In patients with the mutated gene, however, the mutant BRCA1 is not appropriately recruited, and the breaks are not repaired. The mutation thus permits more mutations—like fire fueling fire—until the growth-regulatory and metabolic controls on the cell are snapped, ultimately leading to breast cancer. Breast cancer, even in BRCA1-mutated patients, requires multiple triggers. The environment clearly plays a role: add X-rays, or a DNA-damaging agent, and the mutation rate climbs even higher. Chance plays a role since the mutations that accumulate are random. And other genes accelerate or mitigate the effects of BRCA1—genes involved in repair of the DNA or the recruitment of the BRCA1 protein to the broken strand.
The BRCA1 mutation thus predicts a future, but not in the sense that a mutation in the cystic fibrosis gene or Huntington’s disease gene predicts the future. The future of a woman carrying a BRCA1 mutation is fundamentally changed by that knowledge—and yet it remains just as fundamentally uncertain. For some women, the genetic diagnosis is all-consuming; it is as if their lives and energies are spent anticipating cancer and imagining survivorship—from an illness that they have not yet developed. A disturbing new word, with a distinctly Orwellian ring, has been coined to describe these women: previvors—pre-survivors.
The second case study of genetic diagnosis concerns schizophrenia and bipolar disorder; it brings us full circle in our story. In 1908, the Swiss German psychiatrist Eugen Bleuler