This week marks 30 years since the identification of the BRCA2 gene, a landmark discovery in cancer genetics that has had lasting implications for risk assessment, prevention strategies, and targeted cancer treatment. First reported in 1995, BRCA2 fundamentally changed understanding of inherited susceptibility to breast, ovarian, prostate, and other cancers, and continues to influence modern precision oncology.
The Scientific Context Before BRCA2
The observation that breast cancer could cluster within families dates back to the 1940s, suggesting a hereditary component to disease risk. Over subsequent decades, researchers proposed that rare, high-penetrance genetic alterations were responsible for these familial patterns. This hypothesis gained substantial support in 1990 with the localisation of BRCA1 on chromosome 17.
Following the identification of BRCA1, much of the scientific community focused on refining that discovery. However, it remained unclear whether BRCA1 alone could explain all cases of hereditary breast cancer.
A High-Risk Research Strategy
At the Institute of Cancer Research (ICR) in London, Professor Mike Stratton and colleagues pursued an alternative hypothesis: that an additional high-risk breast cancer susceptibility gene might exist. At the time, this was a scientifically uncertain and high-risk approach.
Evidence supporting this hypothesis emerged through the study of families with strong histories of early-onset breast cancer that could not be explained by BRCA1 mutations. One such family in Ireland, with multiple affected sisters, provided a critical clue that another gene was involved.
Mapping and Identifying BRCA2
Using linkage analysis, the research team searched for shared genetic markers among affected family members. Initial efforts were unsuccessful, requiring the analysis to be repeated in full. Persistence ultimately led to localisation of the gene to chromosome 13.
Identifying the exact gene within this region was particularly challenging, as the human genome had not yet been fully sequenced. The work became increasingly competitive, with parallel efforts underway internationally, including attempts to patent the gene.
Through collaboration with multiple laboratories, including researchers at the Wellcome Sanger Institute, the team successfully identified BRCA2. The discovery was published in Nature in December 1995.
Clinical Implications: Risk Assessment and Prevention
The identification of BRCA2 enabled genetic testing for individuals from families with a history of breast, ovarian, and prostate cancer, allowing more precise assessment of inherited cancer risk. For those found to carry pathogenic variants, this knowledge informed decisions regarding surveillance, preventative surgery, and other risk-reducing strategies.
It is estimated that approximately 3–5 per 1,000 individuals carry pathogenic variants in BRCA1 or BRCA2, with higher prevalence in certain populations. Women with BRCA2 mutations face a substantially increased lifetime risk of breast and ovarian cancer, while men with BRCA2 mutations have a significantly elevated risk of prostate cancer.
Equally important, genetic testing has allowed individuals without pathogenic variants to avoid unnecessary interventions, even in the context of strong family histories.
BRCA2 and Prostate Cancer: Evidence from Screening Studies
The impact of BRCA2 extends beyond breast and ovarian cancer. Pathogenic BRCA2 variants are strongly associated with aggressive forms of prostate cancer, prompting investigation into whether targeted screening could improve outcomes.
One such effort is the IMPACT study, an international clinical trial led by Professor Rosalind Eeles at the ICR. The study evaluates whether regular prostate-specific antigen (PSA) screening in men with inherited genetic alterations, including BRCA2, enables earlier detection of clinically significant prostate cancer.
Participation in this study has demonstrated the potential clinical value of genetically guided screening. In some cases, prostate cancer has been detected in asymptomatic individuals, allowing timely intervention.
Understanding BRCA2 Biology
Following its discovery, research turned to understanding the biological role of BRCA2. Studies revealed that BRCA2 is essential for homologous recombination, a key DNA repair pathway responsible for repairing double-strand DNA breaks.
Loss of BRCA2 function leads to genomic instability, increasing cancer risk. At the same time, this defect creates a therapeutic vulnerability, as BRCA-deficient cells become highly dependent on alternative DNA repair mechanisms for survival.
Targeted Therapy and PARP Inhibitors
This insight led to the development of synthetic lethality based therapies. In 2005, researchers demonstrated that cancer cells with BRCA mutations are particularly sensitive to inhibition of poly(ADP-ribose) polymerase (PARP), an enzyme involved in DNA repair.
PARP inhibitors such as olaparib and rucaparib are now established treatments for BRCA-associated ovarian, breast, prostate, pancreatic, and fallopian tube cancers. These agents have been administered to tens of thousands of patients worldwide and continue to be evaluated in broader populations with DNA repair deficiencies.
A Lasting Scientific Legacy
Beyond BRCA2 itself, the discovery accelerated broader advances in cancer genetics, including polygenic risk modelling and large-scale genomic profiling. These developments have contributed to more refined risk prediction and increasingly personalised approaches to cancer prevention and treatment.
Thirty Years On
Three decades after its discovery, BRCA2 remains central to oncology research and clinical practice. While technological advances such as whole-genome sequencing have transformed the pace of discovery, the BRCA2 story continues to illustrate the long-term impact of high-risk, hypothesis-driven research.
Written by Nare Hovhannisyan, MD