Harmful variants of breast cancer gene identified

Over 3000 genetic variants could disrupt normal function of the RAD51C breast and ovarian cancer gene.

Researchers studied the effect of over 9000 unique changes in the RAD51C gene by altering the DNA of human cells grown in a dish, using a technique known as saturation genome editing. They identified 3094 harmful variants that could increase the risk of cancer, with an accuracy above 99.9 percent when compared to clinical data. The remaining 6045 studied changes were not deemed harmful.

'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. 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', said first author of the paper published in Cell, Rebeca Olvera-León, research assistant at the Wellcome Sanger Institute.

RAD51C usually helps prevent cancer. However, scientists used the genetic data from 421,064 individuals from the UK Biobank and a multi-centre cohort of 8166 ovarian cancer patients to search for the unique changes in RAD51C. They found that there was a significant association between the harmful genetic variants and cancer diagnosis, most notably with hormone-sensitive cancers, such as ovarian cancer.

This study also identified the existence of hypomorphic alleles, a type of variant that reduces the function of RAD51C without fully disabling it. These appear to be more common than previously thought, and they could contribute to breast and ovarian cancer risk. Furthermore, by mapping the protein structure, the researchers identified surface areas of RAD51C essential to its DNA repair function.

Professor Clare Turnbull, clinical lead of the study and consultant in clinical cancer genetics at the Royal Marsden NHS Foundation, said '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.'

There are around 56,800 new breast cancer cases and 7500 new ovarian cancer cases in the UK every year. Genetic testing is common for individuals with a strong family history of cancer, however the health impacts of most RAD51C variants were previously unknown, which can hinder the selection of appropriate medical care. The authors believe this study paves the way for better cancer risk assessment and personalised care.