Researchers at the Wellcome Sanger Institute have discovered over 3,000 genetic changes in the RAD51C gene that significantly increase the risk of breast and ovarian cancer, according to a study published on September 18 in Cell. These harmful variants can raise the risk of ovarian cancer six-fold and aggressive breast cancer four-fold, findings confirmed through analysis of large health databases.
The RAD51C gene plays a critical role in DNA repair, and variants that impair its function are known to heighten cancer risk. Women with defective RAD51C face a 15 to 30 percent lifetime risk of breast cancer and a 10 to 15 percent risk of ovarian cancer. While genetic testing for individuals with a strong family history of cancer is common, the implications of many RAD51C variants have previously been unclear, leading to uncertainty in medical care decisions.
Using a technique called “saturation genome editing,” researchers altered the genetic code of human cells to evaluate 9,188 unique changes in RAD51C. They identified 3,094 variants that may disrupt the gene’s function, achieving over 99.9 percent accuracy in relation to clinical data. Further validation was done using UK Biobank data and an ovarian cancer cohort of over 8,000 individuals.
The study also mapped the protein structure of RAD51C, revealing critical regions necessary for its function and potential interactions with other proteins, which could guide drug development. Additionally, the existence of “hypomorphic alleles,” variants that partially reduce RAD51C function, was highlighted as a significant factor in breast and ovarian cancer risk.
Dr. Rebeca Olvera-León, the study’s first author, emphasized that genetic risk is not a binary condition but exists on a spectrum based on the impact of genetic changes on protein function. This research could lead to improved risk prediction and targeted therapies.
Co-senior author Dr. Andrew Waters noted the importance of analyzing genetic variants within their genomic context to enhance clinical decision-making. Dr. David Adams, also a co-senior author, expressed hopes to extend this approach to other genes, aiming for a comprehensive coverage of the human genome.
Professor Clare Turnbull, the clinical lead, highlighted the potential of these findings to inform diagnostic laboratories in evaluating RAD51C changes and guiding patient management, including enhanced screening and preventive measures.
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