How a twenty-year-old gene discovery is shaping the future of cancer care
Imagine a future where a cancer diagnosis comes with a detailed genetic blueprint, guiding doctors to the most effective, personalized treatment with pinpoint accuracy. This is not science fiction; it's the promise of modern personalized healthcare, and at the heart of this revolution for breast and ovarian cancers are two genes: BRCA1 and BRCA2.
Discovered over twenty-five years ago, these genes were initially recognized for their role in hereditary cancer risk. Today, their significance has exploded, moving beyond risk assessment to directly influence therapy selection and patient outcomes.
The journey "to the future" is one of transforming BRCA testing from a niche genetic service into an integral part of routine clinical practice, ensuring every patient can benefit from the advances in precision medicine 1 . This article explores how scientific discoveries, technological innovation, and new models of care are converging to make this future a reality.
BRCA1 (BReast CAncer gene 1) is a tumor suppressor gene located on chromosome 17. Everyone is born with two copies of this gene, inheriting one copy from each parent.
BRCA2 (BReast CAncer gene 2) is a tumor suppressor gene located on chromosome 13. Like BRCA1, everyone has two copies of this gene.
Their primary job is to produce proteins that play a critical role in repairing damaged DNA within our cells. Think of them as a highly skilled molecular repair crew, constantly fixing errors that could otherwise lead to cancer 2 .
The problem arises when a person inherits a harmful change, or pathogenic variant, in one of these genes. This defective copy means their cellular repair system is already compromised. If the second, healthy copy of the gene becomes altered during their lifetime, the cell can lose all ability to repair certain types of DNA damage, dramatically increasing the likelihood that it will become cancerous 2 .
Carrying an inherited harmful BRCA variant significantly elevates the lifetime risk of several cancers. The chart below compares these risks to the general population 2 .
| Cancer Type | Risk for BRCA1 Carriers | Risk for BRCA2 Carriers | Risk in General Population |
|---|---|---|---|
| Female Breast Cancer | >60% | >60% | ~13% |
| Second Primary Breast Cancer (within 20 years of first) |
30–40% | ~25% | ~8% |
| Ovarian Cancer | 39–58% | 13–29% | ~1.1% |
| Male Breast Cancer (by age 70) |
0.2–1.2% | 1.8–7.1% | ~0.1% |
| Prostate Cancer (by age 80) |
7–26% | 19–61% | ~10.6% |
| Pancreatic Cancer | Up to 5% | 5–10% | ~1.7% |
BRCA carriers face significantly elevated cancer risks
Enhanced screening and preventive measures available
The technology for BRCA testing has evolved rapidly. Early methods, like Sanger sequencing, were time-consuming and could only examine specific parts of the gene.
The advent of Next-Generation Sequencing (NGS) was a game-changer. NGS allows for the rapid, scalable, and cost-efficient analysis of the entire BRCA1 and BRCA2 genes, and can even screen multiple other cancer-risk genes simultaneously 1 .
However, this technological boom also revealed a new challenge: interpretation. As testing became more widespread, laboratories began discovering thousands of rare genetic changes whose clinical significance was unknown. These are classified as Variants of Uncertain Significance (VUS) 3 .
A VUS result is frustrating for patients and clinicians because it cannot be used to guide medical decisions, often leaving people in a state of limbo.
Misclassifying a benign variant as pathogenic can have severe consequences, leading to unnecessary preventive surgeries. A stark example from Norway involved 21 women who underwent prophylactic mastectomies and oophorectomies based on a misclassified BRCA2 variant later found not to be pathogenic 3 .
This highlights the need for national and international collaboration. A Norwegian study found that when four different laboratories compared their classifications of the same BRCA variants, 30% initially disagreed. After dedicated collaboration and data sharing, this discrepancy was reduced to 10%, dramatically improving the consistency and quality of patient care across the country 3 .
To tackle the massive challenge of VUS, scientists are developing high-throughput functional assays. A landmark 2025 study published in Nature exemplifies this approach, focusing on systematically classifying all possible variants in a critical part of the BRCA2 gene 7 .
The researchers used a cutting-edge technique called saturation genome editing (SGE) to test the functional impact of nearly every single-letter change in exons 15-26 of the BRCA2 gene, which encodes its essential DNA-binding domain (DBD).
Nearly every possible single-letter change in the targeted BRCA2 exons
The experiment was highly successful, assigning a functional classification to 99.9% (6,959) of the SNVs tested. The results were calibrated against known pathogenic and benign variants for accuracy 7 .
| Pathogenicity Category | Number of SNVs | Percentage of Total | Key Composition |
|---|---|---|---|
| Benign (Combined) | 5,680 | 81.6% | Mostly missense and silent variants |
| Pathogenic (Combined) | 1,155 | 16.6% | Nonsense, splice-site, and damaging missense variants |
| Variant of Uncertain Significance (VUS) | 124 | 1.8% | Variants with intermediate functional impact |
The clinical impact of this work is profound. By integrating these functional data into existing classification models, the study enabled the confident reclassification of 91% of the evaluated variants as either clearly pathogenic or clearly benign. This provides patients and clinicians with actionable information, resolving the uncertainty that has long plagued genetic testing 7 .
A gene-editing tool used to precisely cut the cellular DNA and insert the variant library into the endogenous BRCA2 gene.
A human cell line with only one set of chromosomes, making it ideal for functional studies of essential genes like BRCA2.
A comprehensive collection of plasmids containing every possible single-nucleotide change in the targeted BRCA2 exons.
High-throughput DNA sequencing technology used to count and quantify each variant in the population.
So, how do these scientific advances translate to the clinic? For a patient, a BRCA test result can directly influence their treatment pathway and personal choices.
Identification of BRCA status
Discussion of results with healthcare team
Personalized treatment plan
Treatment and monitoring
A woman with breast cancer and a pathogenic BRCA variant may opt for a more extensive surgery, such as a double mastectomy, to significantly reduce her very high risk of a new cancer developing in either breast 2 .
The discovery that BRCA-deficient cancer cells are vulnerable to a specific class of drugs called PARP inhibitors (e.g., olaparib, talazoparib) is a cornerstone of precision medicine. BRCA status is now a critical biomarker for determining if a patient will respond to these targeted therapies 1 .
Healthy individuals who discover they carry a BRCA variant can engage in enhanced cancer surveillance and consider risk-reducing surgeries, such as salpingo-oophorectomy (removal of ovaries and fallopian tubes), which has been shown to lower the risk of both ovarian and breast cancer .
Despite the progress, significant challenges remain. Real-world data from the Australian National Gynae-Oncology Registry reveals that while BRCA testing rates are encouraging, disparities exist for older women and those in regional areas. Furthermore, a concerning "evidence-practice gap" exists, where not all patients with a qualifying BRCA mutation subsequently receive the PARP inhibitor therapy for which they are eligible 6 .
Integrating genetic testing into standard oncology care, with oncologists managing pre-test consultations to increase accessibility 1 .
Researchers are developing deep learning models that can predict BRCA status directly from routine histopathology images, potentially offering a rapid and cost-effective pre-screening tool 8 .
As precision medicine matures, studies are confirming that the combination of BRCA testing and subsequent targeted therapy represents a valuable use of healthcare resources by improving patient outcomes 9 .
The journey of BRCA from a known risk gene to a cornerstone of therapeutic decision-making perfectly encapsulates the promise of personalized healthcare. The path "to the future" is paved with interdisciplinary collaboration, technological innovation, and a steadfast commitment to ensuring that these advances reach every patient in need.
By continuing to refine testing practices, resolve genetic uncertainty, and break down systemic barriers, we are moving closer to a world where a person's genetic makeup is seamlessly used to deliver the most effective, individualized care—turning the science of today into the standard practice of tomorrow.
BRCA1 (1994) & BRCA2 (1995)
DNA repair and tumor suppression
>60% for BRCA carriers vs ~13% general population
Up to 7% for BRCA2 carriers vs 0.1% general population
Before the SGE study, a significant portion of BRCA2 variants were classified as VUS, creating clinical uncertainty. The study resolved 91% of these variants 7 .