Breast and ovarian cancer linked to thousands of gene variants

UK scientists have pinpointed thousands of genetic changes in a gene that may increase a person’s risk of developing breast and ovarian cancer, paving the way for better risk assessment and more personalised care. Their findings have been published in the journal Cell.

Researchers from the Wellcome Sanger Institute and their collaborators focused on the ‘cancer protection’ gene RAD51C, known to increase ovarian cancer risk sixfold and risk of aggressive subtypes of breast cancer fourfold. The gene encodes a protein crucial for DNA repair; variants in the gene that stop this protein from working are known to increase the risk of breast and ovarian cancers and may rarely, if there are two harmful gene changes are present, result in the genetic disorder Fanconi anaemia. Women with a faulty RAD51C gene face a 15–30% lifetime risk of developing breast cancer and a 10–15% risk of developing ovarian cancer.

While genetic testing is common for individuals with a strong family history of cancer, the health impacts of most RAD51C variants were previously unknown, leaving patients and doctors often struggling to determine appropriate medical care moving forward. The researchers set out to understand the effect of 9188 unique changes in the RAD51C gene by artificially altering the genetic code of human cells grown in a dish, in a process known as ‘saturation genome editing’.

They identified 3094 of these variants that may disrupt the gene’s function and increase cancer risk, with an accuracy above 99.9% when compared to clinical data. Analysis of UK Biobank data and an ovarian cancer cohort of over 8000 individuals further confirmed the link between these harmful RAD51C variants and cancer diagnoses.

The team also identified crucial surface areas of the RAD51C protein 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, 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.

“This research demonstrates that genetic risk for breast and ovarian cancer isn’t a simple yes-or-no scenario, but exists on a spectrum based on how genetic changes affect protein function,” said first author Rebeca Olvera-León. “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.”

“This work demonstrates the power of analysing genetic variants on a large scale within their genomic context,” added co-senior author Dr Andrew Waters. “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.”

“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,” concluded co-senior author Dr David Adams. “We aim to extend this technique to many other genes, with the goal of covering the entire human genome.”

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