New studies have discovered particular genetic alterations that may heighten an individual’s likelihood of developing breast and ovarian cancers, assisting in clinical decision-making.
Researchers have identified thousands of genetic modifications in a gene that could elevate a person’s chances of developing breast and ovarian cancer, leading to improved risk evaluation and more tailored medical care.
Scientists from the Wellcome Sanger Institute, in collaboration with others, concentrated on the ‘cancer-protective’ gene RAD51C. They found over 3,000 detrimental genetic alterations that might hinder its function, potentially increasing the risk of ovarian cancer by six times and the risk of aggressive breast cancer subtypes by four times. These findings were corroborated by analyzing data from extensive health databases.
Published in Cell on September 18, the research is available for free, allowing healthcare professionals and diagnostic lab scientists to enhance their cancer risk assessments, particularly for those with a family history of these cancers. This reduces the confusion often associated with genetic testing.
The research also identified critical areas of the protein necessary for its function, highlighting new aspects of cancer development and possible targets for treatment.
In the UK, breast cancer stands as the most frequently diagnosed cancer, with approximately 56,800 new cases each year. One in seven women in the UK will receive a breast cancer diagnosis in their lifetime. Ovarian cancer ranks as the sixth most common cancer among women in the UK, accounting for around 7,500 new cases annually.
The RAD51C gene is responsible for coding a protein that plays a critical role in DNA repair. Changes in this gene that impair the protein’s function are known to raise the risk of breast and ovarian cancers. In rare instances, if two harmful gene alterations are present, it may lead to Fanconi Anaemia, a serious genetic disorder. Women with mutations in the RAD51C gene have a lifetime risk of 15 to 30 percent for breast cancer and 10 to 15 percent for ovarian cancer.
Although genetic testing is common for individuals with a significant family history of cancer, the health implications of most RAD51C alterations were not well understood previously. This ambiguity about cancer risk can leave both patients and doctors uncertain about the right medical care moving forward.
In this new research, scientists from the Wellcome Sanger Institute and their team aimed to assess the effects of 9,188 distinct changes in the RAD51C gene. They utilized a method known as ‘saturation genome editing’ to artificially modify the genetic code of human cells grown in laboratory conditions. They discovered 3,094 variants that could influence the gene’s function and heighten cancer risks, achieving over 99.9 percent accuracy when compared to clinical data. Analyses from the UK Biobank data and an ovarian cancer cohort including over 8,000 individuals further validated the association between these harmful RAD51C variants and cancer diagnoses.
By mapping the protein’s structure, the team also pinpointed vital surface regions of RAD51C that are essential for its DNA repair function. These areas may interact with yet-to-be-identified proteins or contribute to processes like phosphorylation, providing key insights for developing new drugs and potential treatment targets.
The research also uncovered ‘hypomorphic alleles’—a type of variant that diminishes the function of the RAD51C gene without entirely disabling it. These variants appear to be more prevalent than previously understood and may significantly raise the risk of breast and ovarian cancers.
Rebeca Olvera-León, the study’s primary author at the Wellcome Sanger Institute, commented, “This research highlights that the genetic risk of breast and ovarian cancer isn’t a straightforward yes-or-no situation, but exists on a spectrum based on how genetic changes impact protein function. A deeper understanding of how RAD51C variants affect cancer risk opens avenues for more precise risk prediction, preventive strategies, and potentially targeted treatments.”
Dr. Andrew Waters, a co-senior author of the study at the Wellcome Sanger Institute, stated, “This work illustrates the benefits of analyzing genetic variants on a large scale within their genomic context. Not only do we gain insights into how cancer-related DNA alterations affect patients, assisting with clinical decisions, but we can also delve into how these variants influence the gene’s function at a detailed molecular level. This enhances our understanding of how proteins operate and how genes evolve over time.”
Dr. David Adams, another co-senior author of the study at the Wellcome Sanger Institute, added, “The strong connection between harmful variants and cancer in substantial studies indicates that this variant classification approach could serve as a valuable asset in personalized medicine and cancer prevention strategies. Our ambition is to expand this methodology to many other genes, aiming to encompass the entire human genome within the next decade through the Atlas of Variant Effects.”
Professor Clare Turnbull, the clinical lead of the study, a Professor of Translational Cancer Genetics at The Institute of Cancer Research, London, and Consultant in Clinical Cancer Genetics at The Royal Marsden NHS Foundation, remarked, “These new findings will greatly benefit diagnostic laboratories in understanding the RAD51C gene alterations detected during clinical genetic testing in cancer patients and their relatives. The assay data will facilitate our ability to discern which gene changes pose risks and which are benign, thus assisting in decisions about which patients should receive additional breast cancer screenings or preventive ovarian surgeries.”
