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Researchers have identified thousands of genetic variants in a single gene that may increase a person’s risk of ovarian and breast cancer, opening the way to more accurate risk assessments and personalized treatments.
Focusing on the “cancer protection” gene RAD51C, researchers at the Wellcome Sanger Institute and their collaborators discovered more than 3,000 harmful genetic changes that may interfere with its function and increase the risk of aggressive subtypes of breast cancer by fourfold and the risk of ovarian cancer by sixfold. Data analysis from extensive health databases validated these findings.
These results, which are openly available and published in Cell, can be used to help medical professionals and clinical laboratory scientists more accurately predict cancer risk, especially in people with a family history of malignant diseases.
The study also identified regions of the protein that are essential for its function, and pointed to new roles in cancer development and potential therapeutic targets.
Breast cancer is the most common cancer in the UK, with around 56,800 new cases diagnosed each year. One in seven women in the UK will be diagnosed with breast cancer in their lifetime2. Ovarian cancer is the sixth most common cancer in women in the UK, with around 7,500 new cases diagnosed each year3.
The RAD51C gene encodes a protein important for DNA repair. Variants in this gene that prevent the protein from working are known to increase the risk of breast and ovarian cancer and, rarely, if two harmful gene changes are present, can cause Fanconi anemia, a serious genetic disorder4. Women with a defective RAD51C gene have a 15 to 30 percent risk of developing breast cancer and a 10 to 15 percent risk of developing ovarian cancer5.
While genetic testing is common for individuals with a strong family history of cancer, the health effects of most RAD51C variants were previously unknown. This uncertainty over cancer risk often leaves patients and doctors struggling to determine appropriate medical care going forward.
In this new study, researchers at the Wellcome Sanger Institute and their colleagues attempted to understand the impact of 9,188 unique changes in the RAD51C gene by artificially altering the genetic code of human cells grown in a dish, a process known as ‘saturation genome editing’. They identified 3,094 of these variants that may disrupt the function of the gene and increase cancer risk, with more than 99.9 per cent accuracy compared with clinical data. Analysis of UK Biobank data and an ovarian cancer cohort of more than 8,000 individuals confirmed the association between these harmful RAD51C variants and cancer diagnosis.
By mapping the protein structure, the team also identified important surface regions of RAD51C that are essential for its DNA repair function. These regions may interact with other, yet-to-be-identified proteins or play a role in processes such as phosphorylation, providing valuable insights for drug development and potential new treatment targets.
The study also revealed the existence of ‘hypomorphic alleles’ – a type of variant that reduces the function of the RAD51C gene without completely inactivating it. These appear to be more common than previously thought and may contribute significantly to breast and ovarian cancer risk.
Rebecca Olvera-Leon, first author of the study at the Wellcome Sanger Institute, said: “This research shows that genetic risk for breast and ovarian cancer is not a simple yes-or-no scenario, but rather is based on how genetic changes affect the function of proteins. With a more comprehensive understanding of how RAD51C genetic variants contribute to cancer risk, this opens up new possibilities for more accurate risk prediction, prevention strategies and potential targeted therapies.”
Dr Andrew Waters, co-senior author of the study at the Wellcome Sanger Institute, said: “This work demonstrates the power of analysing genetic variants at a large scale in their genomic context. Not only can we understand how cancer-related DNA changes affect patients, helping to inform clinical decisions, but we can also explore how these variants affect gene function at a detailed molecular level. This provides important information about how proteins work and how genes evolve over time.”
Dr David Adams, co-senior author of the study at the Wellcome Sanger Institute, said: “The strong association between harmful variants and cancer in large studies suggests that this approach to variant classification could be a valuable tool in personalised medicine and cancer prevention. We aim to extend this technique to many other genes, with the goal of covering the whole human genome through the Atlas of Variant Effects over the next decade.”
Professor Clare Turnbull, clinical lead of the study, Professor of Translational Cancer Genetics at The Institute of Cancer Research, London, and Consultant in Clinical Cancer Genetics at The Royal Marsden NHS Foundation, said: “These new data will be highly useful for diagnostic laboratories to better understand the RAD51C gene changes we identify on clinical genetic testing in cancer patients and their family members. The assay data will help us conclude which gene changes are harmful and which are harmless. This aids our decision-making about which patients may benefit from being offered additional breast cancer screening and preventive surgery of the ovaries.”
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