Researchers have identified thousands of genetic variations that could raise the risk of breast and ovarian cancers. The discovery may improve risk assessments and lead to more tailored medical care for individuals with a family history of these cancers.
Scientists from the Wellcome Sanger Institute and their collaborators focused on the RAD51C gene, which is known for its role in protecting against cancer. Mutations in this gene have been linked to a sixfold increase in ovarian cancer risk and a fourfold rise in aggressive breast cancer types. The research identified over 3,000 potentially harmful genetic changes that may disrupt RAD51C’s function, raising the risk of cancer.
These findings, published today in the journal Cell, are now available for medical professionals to use in genetic testing. This could reduce the uncertainty patients often face when trying to assess their cancer risk, especially those with a strong family history of breast or ovarian cancer.
The research also highlights key regions of the RAD51C protein that are crucial for DNA repair. Understanding these regions may offer new targets for cancer therapies in the future.
Breast and ovarian cancer in the UK
Breast cancer is the most common cancer in the UK, with around 56,800 new cases annually. One in seven women will be diagnosed with breast cancer during their lifetime. Ovarian cancer is less common but still significant, with about 7,500 cases reported each year in the UK.
The RAD51C gene plays a key role in repairing damaged DNA. When this gene is altered, it may fail to work properly, leading to an increased risk of cancer. Women with certain RAD51C variants face up to a 30% lifetime risk of breast cancer and up to 15% risk for ovarian cancer.
Although genetic testing is widely available for individuals with a family history of cancer, the health impact of many RAD51C variants has been unclear until now. This uncertainty has made it difficult for doctors and patients to decide on the best course of action.
Rebecca Olvera-León, the study’s lead author, points out that genetic risk for breast and ovarian cancer isn’t black and white. “This research demonstrates that genetic risk for breast and ovarian cancer isn’t a simple yes-or-no scenario,” she explains, “but exists on a spectrum based on how genetic changes affect protein function.” The hope is that with a more comprehensive understanding of how these genetic variants contribute to cancer risk, it will open up new possibilities for more accurate risk prediction, preventive strategies, and even develop targeted treatments.
Groundbreaking research using genome editing
In the study, researchers used a technique called “saturation genome editing” to test the effects of 9,188 unique changes to the RAD51C gene. They identified over 3,000 variants that could increase cancer risk, with an accuracy rate of more than 99.9% when compared to real-world clinical data. The findings were further validated using data from large-scale health studies, such as the UK Biobank.
Dr Andrew Waters, co-senior author of the study says large-scale studies like this help scientists understand how genetic changes impact both patients and the genes themselves. “Not only can we understand how cancer-related DNA changes affect patients, helping with clinical decisions, but we can also explore how these variants impact the gene’s function at a detailed molecular level. This provides important insights into how proteins work and how genes evolve over time.”
The team also mapped the structure of the RAD51C protein, revealing critical areas needed for its DNA repair function. These findings could help guide the development of new cancer treatments by targeting these regions.
Additionally, the study uncovered a type of variant known as a “hypomorphic allele.” These gene changes weaken, but don’t completely disable, RAD51C’s function. They could play a significant role in raising cancer risk, even though they haven’t been fully recognised before.
Moving towards personalised medicine
Dr. David Adams, another senior author, points to the potential of this research for personalised medicine. He says the strong link between harmful gene variants and cancer shows that their approach to classification could be a valuable tool in cancer prevention. “We aim to extend this technique to many other genes,” he explains, “with the goal of covering the entire human genome in the next decade through the Atlas of Variant Effects”. This is an international collaboration that aims to create maps of the effects of genetic variants on the human genome.
Professor Clare Turnbull, clinical lead for the study, noted that these findings will be especially helpful in clinical settings. These new insights will allow diagnostic labs to better identify harmful gene changes in cancer patients and their family members undergoing genetic testing. “The assay data will help us to conclude which gene changes are harmful and which are innocent,” she explains. “This aids our decision-making regarding which patients might benefit from offer of extra breast cancer screening and preventive surgery of the ovaries.”
The researchers plan to extend this work to cover more genes in the coming years, with the aim of improving risk prediction for a wide range of genetic conditions. The study was supported by Wellcome and Cancer Research UK, the world’s leading cancer charity dedicated to saving lives through research.
This article is adapted from a press release by the Wellcome Sanger Institute at Cambridge University.
