The \(BRCA\) genes, \(BRCA1\) and \(BRCA2\), are human genes whose inherited mutations significantly elevate the lifetime risk for certain cancers, particularly breast and ovarian cancer. These genes encode tumor suppressor proteins that help repair damaged DNA, maintaining the stability of the cell’s genetic material. The discovery of these genes resulted from a decades-long scientific effort involving multiple research groups to identify and clone these hereditary cancer susceptibility genes.
Laying the Groundwork: Early Evidence of Inherited Risk
The concept that breast cancer could be inherited had been observed for centuries, but scientific proof of a single, highly penetrant gene was elusive until the late 20th century. American geneticist Mary-Claire King began studying families with high rates of early-onset breast cancer in the 1970s, using epidemiological data to hypothesize a genetic link. Her persistence in applying complex mathematical and statistical models to pedigree data helped advance the field.
King’s team used linkage analysis to find a marker that co-segregated with the disease across many generations. In 1990, she successfully mapped the location of the first major breast cancer susceptibility gene to a specific region on the long arm of Chromosome 17. King named this chromosomal neighborhood \(BRCA1\) (BReast CAncer gene 1), though the gene itself had not yet been isolated or sequenced.
Identifying the BRCA1 Gene
King’s localization of the \(BRCA1\) region on Chromosome 17 triggered an international effort to physically isolate, or “clone,” the gene. Identifying the precise gene sequence involved numerous academic and commercial laboratories. The team that succeeded in cloning and sequencing \(BRCA1\) was led by Mark Skolnick and Jeff O’Connell at the University of Utah, working with the biotechnology company Myriad Genetics.
In September 1994, the Utah/Myriad team published the gene sequence, officially identifying \(BRCA1\). The cloning involved identifying a novel gene within the narrow chromosomal area mapped by King’s group. This provided the full genetic blueprint, confirming that mutations in this large gene increased the risk for hereditary breast and ovarian cancer.
Pinpointing the BRCA2 Gene
Following the discovery of \(BRCA1\), statistical evidence suggested that mutations in this gene did not account for all cases of inherited breast cancer. This led to a new search for \(BRCA2\) on a different chromosome.
The successful identification of \(BRCA2\) was achieved by a large, international collaboration based primarily in the United Kingdom. This effort was led by Mike Stratton and Richard Wooster at The Institute of Cancer Research in London. They located and cloned the \(BRCA2\) gene on Chromosome 13, publishing their findings in late 1995. The discovery confirmed that hereditary breast cancer was genetically heterogeneous, with mutations in either gene predisposing individuals to breast, ovarian, and prostate cancer.
The Impact of the BRCA Gene Discoveries
The identification of \(BRCA1\) and \(BRCA2\) changed the clinical management of hereditary cancer risk. Commercial genetic testing became available quickly to screen individuals for inherited mutations in these genes. This allowed people with a strong family history to learn their risk and pursue preventative measures, such as enhanced screening or prophylactic surgery.
The discoveries also initiated a legal controversy over gene patenting. Myriad Genetics, which was involved in the \(BRCA1\) discovery, obtained exclusive patents on the isolated \(BRCA1\) and \(BRCA2\) gene sequences, controlling commercial testing in the United States for nearly two decades. This monopoly was challenged in court, and in 2013, the U.S. Supreme Court ruled that naturally occurring human genes cannot be patented. This decision opened the door for broader access to genetic testing and increased research into these genes.