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.