Breast cancer is a common complex disease, and until Mary-Claire King’s work, the prevailing view was that such diseases arise from interactions among multiple genetic and environmental factors. But she was intrigued by hints that there might be inherited forms of breast cancer and beginning in 1974, long before there were genomic tools for human genetic analysis, she tested this head-on by studying more that 1500 families, each identified through one woman with breast cancer. Using a mathematical approach, she determined that clustering of breast cancer in these families occurred more frequently than expected by chance, and that this clustering could be best explained by the presence of mutations in an unknown gene that greatly increased risk in about 4 % of families. By studying patterns of breast and ovarian cancer in families, she predicted that among women carrying mutations in this hypothetical gene, the risk of breast cancer would be about 80% by age 70, ten times more than among women in the same families without any mutation in this hypothetical gene.

The field was skeptical about her mathematical model so she set out to prove that her hypothetical gene existed, by mapping it to an exact chromosomal location. Toward this end, King analyzed DNA from hundreds of women in 23 families very severely affected with breast cancer. In many of these families, breast cancer struck young women, often in both breasts, and in some families, breast cancer even occurred in men. Finding the home of the hypothetical gene was difficult for multiple reasons. First, most cases of breast cancer are not familial. Might the critical mutations be inherited from unaffected fathers as well as from mothers with the disease? Second, breast cancer is common, so common that both inherited and non-inherited cases could occur in the same families. Third, breast cancer might not strike all women who carry a high-risk gene; some might be fortunate. And fourth, different families might carry different high-risk genes. No one had previously tackled such complexities, and an attempt to unearth a breast cancer gene seemed woefully naïve.

King was not dissuaded by these challenges, and by late 1990, she had found the home of her breast cancer gene. She identified a section of chromosome 17 that carried definitive genetic markers, or signposts, in women with breast cancer in the most severely affected families. Somewhere in that stretch of DNA lay the gene, which she named BRCA1.

King’s announcement revolutionized an entire field. Geneticists who had dismissed the notion that a disease as complex as breast cancer could be linked to any one gene started pursuing that very gene using positional cloning, the only possible approach before the Human Genome Project. Four years later, the gene was cloned by a commercial lab. King’s discovery of the existence of the gene and the identification of its chromosomal position was the key to cloning it. Alterations in BRCA1 and in a second breast-cancer susceptibility gene, BRCA2, cloned shortly later, increase risk of both breast and ovarian cancer. The proteins encoded by these genes repair broken DNA. When the BRCA1 or BRCA2 proteins fail to perform their jobs, genetic integrity is compromised, setting the stage for cancer.

King subsequently showed that the risks of breast and ovarian cancer among women with mutations in BRCA1 are very high – up to 80% lifetime risk for breast cancer and 50% lifetime risk for ovarian cancer. She also showed that risks have increased over the decades for non-genetic reasons.

In order to enable all patients to be tested for mutations in these genes, King and her group developed a multi-gene platform (named BROCA, in honor of the 19th century French surgeon who first described familial breast cancer) to simultaneously detect all classes of mutations in all breast and ovarian cancer genes. This platform has been put into clinical use worldwide. As a direct result of her efforts, there now exist tests for mutations in BRCA1 and in all other breast cancer genes. Millions of women worldwide have benefitted from these tests.

King’s approach to gene discovery for breast cancer is a model for the discovery of genes responsible for many common complex diseases. The paradigm is to identify rare families in which the complex disease characteristics are inherited. Identification of the gene critical to the disease pathology in such families both reveals disease mechanisms and provides the genetic basis for identification of mutations in patients with little or no family history of the disease. In addition to being applied to millions of women worldwide at risk of breast and ovarian cancer, this approach has been the basis for gene discovery in diabetes, colon cancer, coronary artery disease, hypertension, Alzheimer’s disease, Parkinson’s disease and other complex traits. Meanwhile, for breast and ovarian cancer, the results of her work have saved the lives of countless women.

26 September 2018 Hong Kong