Thirty years since the race to the BRCA1 gene

It had long been suspected that the occurrence of breast cancer had a familial component, but early studies were confounded by the complexity of the disease. However, in 1990, researchers identified a key genetic determinant of inherited breast cancer risk1, which fired the starting gun for what turned out to be a four-year race to identify the underlying gene. This was achieved when Miki et al., in a 1994 paper in Science2, described a previously unknown gene in which affected individuals in high-risk families carried deleterious mutations. The work provided strong evidence that this was indeed the BRCA1 gene.
Read the paper: A Strong Candidate for the Breast and Ovarian Cancer Susceptibility Gene BRCA1
BRCA1 was identified using positional cloning, a method to identify a gene using genetic linkage to a specific disorder and chromosomal location. No previous knowledge of the gene’s function or structure was required with this approach. Those who were involved in the isolation of genes by positional cloning will recall the slow and painstaking methods required before the sequence of the human genome had been elucidated.
Pioneering researchers1 had mapped BRCA1 to a specific part of human chromosome 17, but the region was large. Several groups undertook the genetic refinement of the region, the identification of candidate genes and the search for mutations in these genes in affected families. Miki and colleagues searched a 600-kilobase genomic region for expressed genes, and identified one made up of 22 protein-coding segments that produced a previously undescribed protein of 1,863 amino acids in length. The researchers identified mutations of different types in this gene, the two most compelling of which — known as frameshifts and termination codons, which both prematurely truncate the BRCA1 protein — were associated with the occurrence of breast cancer in high-risk families. On the basis of these data, the paper describes this gene as a candidate for BRCA1; overwhelming subsequent evidence indicated that this was indeed the culprit.
Super-speedy sequencing puts genomic diagnosis in the fast lane
The immediate effect of the identification of BRCA1, and BRCA2, which was identified a year later3, was that it provided a way of ascertaining which individuals in high-risk families carried mutations. Both are tumour-suppressor genes and at-risk individuals have a single mutant copy, the normal copy being lost during cancer development. Before the genes had been isolated, risk assessment was based on family history, which could not distinguish the roughly half of individuals in an affected family who were mutation carriers from the rest who were not. The ability to confirm mutations in BRCA genes meant that prophylactic surgery, which involves removal of the breasts and ovaries, could be adopted as a risk-reduction strategy. As subsequent work demonstrated, this was effective at saving lives4.
At the same time as the gene was isolated, a patent for the DNA sequence of BRCA1 was filed by the US genetic-testing company Myriad Genetics, restricting who could perform tests for mutations. This led to a widespread societal discussion around the appropriateness of patenting human genome sequences. The debate was effectively ended by the decision of the US Supreme Court in 2013, in the Association for Molecular Pathology v. Myriad Genetics case, to disallow the patenting of naturally occurring DNA sequences. Essentially, human genes could not become intellectual property5. Importantly, the case was brought using the BRCA1 and BRCA2 genes as exemplars of naturally occurring DNA sequences.
The DNA sequence of the BRCA1 gene determined by Miki et al. revealed little about the function of the encoded protein; the BRCA2 gene was similarly uninformative. An early clue about function was provided in 1997 when researchers showed6 that the BRCA1 protein associated with a protein called RAD51, which had previously been shown to be crucial for accurate DNA recombination, the exchange of DNA between chromosomes.
What’s next for PARP inhibitors?
Years of subsequent work by numerous groups mechanistically implicated both BRCA1 and BRCA2 in the maintenance of genome integrity. In 1999, researchers demonstrated7 a specific role for BRCA1 in fixing double-strand DNA breaks by a high-fidelity method of DNA repair called homologous recombination. Although other roles in cancer development cannot be ruled out, this work suggested that the underlying cause of the increased cancer incidence in carriers of mutations in BRCA1 and BRCA2 was, at least in part, through impaired DNA repair, enhancing the rate of mutation genome-wide.
One of the main driving forces for isolating disease-linked genes has been the hope that it might reveal information that could open up new avenues for treatment — in this case, tailored therapeutic approaches for tumours arising in carriers of BRCA mutations. However, these genes are tumour suppressors, and their role in cancer development involves a loss of function. It was therefore unclear how effective therapeutics might be developed, given that restoring the activity of the proteins in a tumour seemed impracticable.
In 2005, scientists reported that inhibition of another protein involved in DNA repair, the enzyme poly(ADP-ribose) polymerase (PARP), resulted in the death of cancer cells that already had an impaired DNA-repair system caused by the loss of BRCA1 or BRCA2 function. The discovery of this ‘synthetic lethal’ interaction between PARP inhibition and BRCA1 and BRCA2 mutations ushered in a new therapeutic approach8–10. After almost 10 years of clinical development, and 20 years after the publication of the paper by Miki et al., PARP inhibitors were approved by the US Food and Drug Administration as a treatment for ovarian tumours with BRCA1 or BRCA2 mutations. Subsequent clinical approvals were made for advanced breast, prostate and pancreas cancer and then, in 2022, for early-stage breast cancer11 (Fig. 1).
What might be the future of this field? There is merit in considering screening for mutations in BRCA genes in the general population lacking a strong family history of cancer. This issue is controversial owing to concerns over logistics and risk versus benefit, but with advances in technology and risk assessment, widespread screening seems likely to happen eventually. The development of approaches to prevent cancer arising in mutation carriers through specific therapeutic interventions or vaccination is also under active consideration. Finally, although gene-editing technologies such as CRISPR are not yet appropriate for correcting BRCA mutations in humans, this might be a possibility in the future12.