Over 5000 high-risk cancer gene variants identified

Researchers from the Wellcome Sanger Institute, The Institute of Cancer Research, London and the University of Cambridge have assessed the health impact of all possible genetic changes in the so-called ‘tumour protection’ gene, BAP1. They found that around one-fifth — or over 5000 — of these possible changes are pathogenic, significantly increasing the risk of developing cancers of the eye, lung lining, brain, skin and kidney.

The BAP1 protein acts as a powerful tumour suppressor in the body, protecting against cancers of the eye, lung lining, brain, skin and kidney. Inherited variants that disrupt the protein can increase a person’s lifetime risk of developing these cancers by up to 50%, typically occurring around middle age.

Detecting these variants early through genetic screening can guide preventative measures, greatly enhance treatment effectiveness and improve quality of life for individuals affected. However, until now, there has been limited understanding of which specific genetic changes in BAP1 to look out for, especially for rare variants that cause it to malfunction and fuel cancer growth.

The researchers tested 18,108 DNA changes in the BAP1 gene by artificially altering the genetic code of human cells grown in a dish, in a process known as ‘saturation genome editing’. They identified that 5665 of these changes were harmful and disrupted the protein’s protective effects. Analysis of UK Biobank data confirmed that individuals carrying these harmful BAP1 variants are over 10% more likely to be diagnosed with cancer than the general population.

The team also discovered that people with harmful BAP1 variants have elevated levels of IGF-1 — a hormone linked to both cancer growth and brain development — in their blood. Even individuals without cancer showed these elevated levels, suggesting that IGF-1 could be a target for new treatments to slow down or prevent certain cancers. Further analysis revealed harmful BAP1 variants and higher IGF-1 levels were linked to worse outcomes in uveal melanoma patients, highlighting the potential for IGF-1 inhibitors in cancer therapy.

“Previous approaches for studying how variants effect function in genes have been on a very small scale, or exclude important contexts that may contribute to how they behave,” said first author Dr Andrew Waters, from the Wellcome Sanger Institute. “Our approach provides a true picture of gene behaviour, enabling larger and more complex studies of genetic variation. This opens up new possibilities for understanding how these changes drive disease.”

The team’s findings, published in the journal Nature Genetics, are freely available so that they can be immediately used by doctors to help diagnose patients and choose the most effective therapies for them. Notably, their technique profiles all possible BAP1 variants from diverse populations — not only those prevalent in European clinical records — helping to address the underrepresentation of non-European populations in genetic studies.

“We want to ensure that life-saving genetic insights are accessible and relevant to all people, regardless of their ancestry,” said senior author Dr David Adams, from the Wellcome Sanger Institute. “Our aim is to apply this technique to a wider range of genes, potentially covering the entire human genome in the next decade with the Atlas of Variant Effects.”

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