The BRCA genes (BReast CAncer genes) are tumor suppressor genes that fix damaged DNA within cells. When these genes contain harmful changes, or mutations, they cannot perform this repair function correctly, which significantly increases a person’s lifetime risk of developing certain cancers, most notably breast and ovarian cancer. The discovery of these genes represented a shift in the understanding of hereditary disease, moving the focus from statistical risk assessment to identifying a specific genetic cause. Exploring the history of this discovery reveals a rapid progression from recognizing a familial pattern to isolating the genes that allow for modern genetic testing.
Early Understanding of Hereditary Cancer
Long before scientists could pinpoint the specific genes, clinicians and researchers had observed a strong pattern of cancer clustering within certain families. This familial incidence, which often included multiple relatives developing breast and ovarian cancers at younger-than-average ages, pointed toward a powerful, inherited factor. Early epidemiological studies in the 19th and 20th centuries documented these family histories, suggesting a direct hereditary component to the disease.
The scientific hypothesis focused on the idea that a single, high-risk gene was being passed down through generations, following an autosomal dominant pattern of inheritance. This belief led to a new type of research called linkage studies, which used genetic markers to track the inheritance of the disease through large, multi-generational families. These studies were designed to map the location of the unknown gene to a specific region on a human chromosome. By the early 1990s, this work had successfully narrowed the search for the first major breast cancer gene to a precise location on the long arm of chromosome 17.
The Pinpointing of BRCA1
The years of meticulous linkage analysis culminated in the isolation of the first gene in 1994. The gene, named BRCA1, was officially identified through the process of positional cloning. This technique involved isolating a gene based solely on its location on a chromosome, using the regional map created by earlier linkage studies.
In September 1994, a team of US scientists, including Mark Skolnick, published the foundational paper announcing the cloning and sequencing of the BRCA1 gene. The identification of BRCA1 on chromosome 17q21 confirmed that this gene was responsible for a substantial portion of inherited breast and ovarian cancers. Although Mary-Claire King’s group had previously mapped the location to chromosome 17 in 1990, the full gene sequence was published by the competing team. This discovery established BRCA1 as a tumor suppressor gene that functions in DNA repair.
Identifying BRCA2
The identification of BRCA1 did not account for all families with a strong history of hereditary breast cancer, suggesting the existence of at least one other major susceptibility gene. Researchers quickly began searching for this second factor in families whose cancer risk was not linked to BRCA1. This focused effort led to the discovery of BRCA2 just over a year later, in December 1995.
A team of researchers, primarily based at the Institute of Cancer Research in London and the Sanger Institute, successfully mapped and cloned the BRCA2 gene. They pinpointed its location on the long arm of chromosome 13, specifically at 13q12.3. The BRCA2 gene was also found to be a tumor suppressor involved in DNA repair, though its protein structure and specific interactions were distinct from BRCA1. BRCA2 mutations were found to be associated with a slightly different cancer spectrum, including a higher association with male breast cancer and pancreatic cancer.
Immediate Impact on Genetic Screening
The dual discovery of BRCA1 and BRCA2 fundamentally transformed the approach to cancer risk assessment and prevention. Before 1994, risk was estimated using family history and statistical models alone; the ability to sequence the genes meant that risk assessment could transition from being statistical to being molecularly precise. Clinical testing for BRCA1 and BRCA2 mutations became available shortly after their discovery, with the first commercial tests brought to market in 1996. This new testing capability created an immediate need for genetic counseling to help individuals understand complex test results and the implications for their health and family planning. The patenting of the gene sequences in the United States became a significant public controversy, raising questions about access to testing and the ethics of proprietary control over human genes.