Scientists identify over 5,000 high-risk cancer gene variants

Scientists have identified more than 5,000 genetic mutations that enable certain cancers to grow, as well as potential therapeutic targets to treat these cancers or prevent them from developing.

Researchers from the Wellcome Sanger Institute, along with collaborators from the Institute of Cancer Research, London and the University of Cambridge, assessed the health impact of any genetic changes in “tumor defence” genes. BAP1The researchers found that about one-fifth of these possible changes are pathogenic and significantly increase the risk of developing cancer of the eye, lung lining, brain, skin and kidney.

The survey results announced today (July 5th) are: Nature Genetics“The results are available free of charge and can be used immediately to help doctors diagnose their patients and select the most effective treatments. Importantly, because all possible mutations were evaluated, the findings will benefit people from diverse ethnic backgrounds who have previously been underrepresented in genetic studies.”

The research team also identified specific destructive BAP1 Genetic mutations and elevated levels of the hormone and growth factor IGF-1. This discovery paves the way for the development of new drugs that could counter these harmful effects and potentially slow or prevent the progression of certain cancers.

The BAP1 protein acts as a powerful tumor suppressor in the body, preventing cancer of the eye, lung lining, brain, skin and kidneys. Inherited mutations that disrupt this protein can increase the lifetime risk of developing these cancers by up to 50 percent, and usually occur during middle age.

Early detection of these mutations through genetic testing could guide preventive measures, significantly improve treatment outcomes, and improve the quality of life for affected people. However, until now, it has not been clear which genetic mutations cause this disease. BAP1 In particular, rare variants that cause dysfunction and promote cancer growth are of particular concern.

Researchers from the Sanger Institute, along with collaborators from the Cancer Research Institute and the University of Cambridge, BAP1 The team artificially altered the genetic code of human cells grown in a dish, using a technique called saturation genome editing. They found that 5,665 of the alterations were harmful and blocked the protein's protective effects. Analysis of data from the UK Biobank showed that individuals with these harmful alterations: BAP1 People with the variant are more than 10 percent more likely to be diagnosed with cancer than the general population.

The research team also found that harmful BAP1 The mutants had elevated blood levels of IGF-1, a hormone linked to both cancer growth and brain development, even in people without cancer, suggesting that IGF-1 may be a potential therapeutic target for slowing or preventing the progression of certain cancers. BAP1 Mutations and elevated IGF-1 levels were associated with worse uveal outcome. Malignant melanoma This suggests that IGF-1 inhibitors may be an effective cancer treatment for patients.

In particular, this technology BAP1 It collects variants that are prevalent in European clinical records, as well as variants from diverse populations, helping to address the underrepresentation of non-European populations in genetic studies.

“Previous approaches to studying how genetic variants affect gene function have either been very small-scale or excluded important context that may contribute to gene behavior. Our approach provides a true picture of gene behavior and enables larger, more complex studies of genetic variants. This opens up new possibilities for understanding how these changes cause disease.”

First study author Dr Andrew Waters of the Wellcome Sanger Institute

Professor Claire Turnbull, clinical lead on the study, Professor of Translational Cancer Genetics at the Institute of Cancer Research, London and Consultant Clinical Cancer Genetics at the Royal Marsden NHS Trust Institute, said: “This research could mean more accurate interpretation of genetic tests, earlier diagnoses and better outcomes for patients and their families.”

Dr David Adams, lead study author from the Wellcome Sanger Institute, said: “We want to ensure that life-saving genetic insights are accessible and relevant to everyone, regardless of ancestry. Our aim is to apply this technology to a wider range of genes, covering the entire human genome with the Variation Effects Atlas over the next decade.”