Researchers have identified thousands of genetic changes in a gene that may increase the risk of developing breast and ovarian cancers, according to a recent study published by Olvera-León et al in Cell. The findings may pave the way for better risk assessment and more personalized care.
Background
Breast cancer and ovarian cancer are among some of the most common cancer types.
The RAD51C gene is responsible for encoding a protein crucial for DNA repair. Variants in this gene are known to increase the risk of ovarian cancer sixfold and aggressive subtypes of breast cancer fourfold. Rarely, if there are two harmful gene changes present, this may result in Fanconi anemia, a severe genetic disorder. Women with a RAD51C gene variant may face a 15% to 30% lifetime risk of developing breast cancer and a 10% to 15% risk of developing ovarian cancer.
Although genetic testing is typical among patients with a strong family history of cancer, the health impacts of most RAD51C gene variants were previously unknown. This uncertainty over cancer risk can leave patients and physicians unable to determine the most appropriate medical care.
Study Methods and Results
In the study, the researchers sought to understand the effects of 9,188 unique changes in the RAD51C gene by artificially altering the genetic code of human cells grown in a dish, known as saturation genome editing.
The researchers discovered 3,094 harmful genetic variants that could potentially disrupt the function of the RAD51C gene and increase the risk of cancer with an accuracy greater than 99.9% compared with clinical data. They then used UK Biobank data and an ovarian cancer cohort of over 8,000 patients to confirm the link between the harmful RAD51C gene variants and cancer diagnoses.
Further, by mapping the protein structure, the researchers identified crucial surface areas of RAD51C that may be essential for its DNA repair function. These regions may interact with other, currently unidentified proteins or play a role in processes such as phosphorylation, offering valuable insights for drug development and potential new treatment targets.
The researchers also revealed the existence of hypomorphic alleles—a type of variant that reduces the RAD51C gene’s function without completely disabling it. These appeared to be more common than previously thought and may significantly contribute to the risk of breast and ovarian cancers.
“The strong connection between harmful variants and cancer in large studies suggests that this approach to variant classification could be a valuable tool in personalized 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,” noted co–senior study author David Adams, PhD, FMedSci, of the Wellcome Sanger Institute.
Conclusions
“This 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 impa ct the gene’s function at a detailed molecular level. This provides important insights into how proteins work and how genes evolve over time,” emphasized co–senior study author Andrew Waters, PhD, of the Wellcome Sanger Institute.
“This research demonstrates that genetic risk for breast and ovarian cancers isn’t a simple yes-or-no scenario but exists on a spectrum based on how genetic changes affect protein function. 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 potentially targeted therapies,” highlighted lead study author Rebeca Olvera-León, MPhil, of the Wellcome Sanger Institute.
The researchers hope their findings can help physicians and diagnostic laboratory scientists better assess the risk of cancer—especially among patients with a family history of breast or ovarian cancer—and reduce the uncertainty that often accompanies genetic testing.
“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 patients [with cancer] 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,” concluded co–study author Clare Turnbull, PhD, Professor of Translational Cancer Genetics at The Institute of Cancer Research in London and a consultant in Clinical Cancer Genetics at The Royal Marsden National Health Service Foundation Trust.
DISCLOSURE: The research in this study was supported by the Wellcome Sanger Institute and Cancer Research UK. For full disclosures of the study authors, visit cell.com.
