Scientists pinpoint thousands of gene variants linked to breast and ovarian cancer risk

Researchers from the Wellcome Sanger Institute and their collaborators focused on the 'cancer protection' gene RAD51C, finding over 3,000 harmful genetic changes that could potentially disrupt its function and increase ovarian cancer risk six-fold and risk of aggressive subtypes of breast cancer four-fold. These findings were confirmed by analyzing data from large-scale health databases.

The study also identified regions of the protein essential for its function, pointing to new roles in cancer development and potential therapeutic targets.

While genetic testing is common for individuals with a strong family history of cancer, the health impacts of most RAD51C variants were previously unknown. This uncertainty over cancer risk often leaves patients and doctors struggling to determine appropriate medical care moving forward.

By mapping the protein structure, the team also identified crucial surface areas of RAD51C 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, offering 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 RAD51C gene's function without completely disabling it. These appear to be more common than previously thought and may significantly contribute to breast and ovarian cancer risk.

Dr. Andrew Waters, co-senior author of the study, Wellcome Sanger InstituteThis work demonstrates the power of analyzing genetic variants on a large scale within their genomic context. 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."

Dr. David Adams, co-senior author of the study at the Wellcome Sanger Institute, said: "The strong connection 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 entire human genome in the next decade through the Atlas of Variant Effects."

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 that we identify on clinical genetic testing in cancer patients and their family members. The assay data will help us to conclude which gene changes are harmful and which are innocent. This aids our decision making regarding which patients might benefit from offer of extra breast cancer screening and preventive surgery of the ovaries."

Source:

Wellcome Trust Sanger Institute

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