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Over 5,000 BAP1 variants linked to specific cancers have been identified, along with a potential therapeutic target to treat or even prevent these cancers. The massive gene screen was done by researchers from the Wellcome Sanger Institute, and their collaborators at The Institute of Cancer Research, London, and the University of Cambridge.

The team used saturation genome editing (SGE) to assess the health impact of all possible genetic changes in the “tumor protection” gene, BAP1. They found around a fifth of the 5000+ possible changes were pathogenic, significantly increasing the risk of developing cancers of the eye, lung lining, brain, skin, and kidney. They also showed that disruptive germline BAP1 variants were significantly associated with higher circulating levels of the mitogen IGF-1, pointing to a possible therapeutic target.

Clare Turnbull, clinical lead of the study, professor of translational cancer genetics at The Institute of Cancer Research, London, said, “This research could mean more accurate interpretation of genetic tests, earlier diagnoses and improved outcomes for patients and their families.”

The findings, published 5 July in Nature Genetics, are freely available to doctors to help diagnose patients and choose the most effective therapies for them. Since all possible variants were assessed in this study, the findings should benefit individuals from diverse ethnic backgrounds.

The BAP1 protein acts as a powerful tumor 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 percent, typically occurring around middle age.  

These researchers tested all 18,108 possible DNA changes in the BAP1 through gene saturation genome editing—artificially altering the genetic code of human cell lines. They found that 5,665 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 ten per cent more likely to be diagnosed with cancer than the general population.

People with harmful BAP1 variants, the team discovered, have elevated levels of IGF-1 in their blood, a hormone linked to both cancer growth and brain development. 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. Other 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.

Notably, the 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.

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

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