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Scientists have discovered more than 5,000 genetic variations that help certain deadly diseases develop, as well as a potential therapeutic target to treat these cancers or even prevent them from arising.
Researchers from the Wellcome Sanger Institute, The Institute of Cancer Research, London and the University of Cambridge evaluated the health effects of genetic changes in BAP1, a ‘tumour defence’ gene. They found that around a fifth of these possible mutations were pathogenic, significantly increasing the risk of developing fatal diseases in the eye, lung lining, brain, skin and kidney.
Gene types of cancer:
The findings, published in Nature Genetics, are freely available so doctors can use them immediately to diagnose patients and choose the most effective treatments for them1. Importantly, because all possible variants were assessed, the findings benefit individuals from diverse ethnic backgrounds, who have historically been underrepresented in genetics research.
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The team also detected a link between certain disruptive BAP1 variants and higher levels of IGF-1, a hormone and growth factor. This finding opens the door to the development of new drugs that could block these harmful effects, potentially slowing or stopping the progression of some cancers.
The BAP1 protein acts as a powerful tumor suppressor in the body, protecting against cancers of the eye, lung lining, brain, skin, and kidney. Hereditary variants that disrupt the protein can increase the risk of developing these cancers by up to 50 percent2, usually occurring around middle age.
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Early detection of these variants through genetic screening could guide preventive measures, increase the effectiveness of treatments and improve the quality of life of affected individuals. However, until now, there has been limited understanding about which specific genetic changes in BAP1 should be looked for, especially for rare variants that make it worse and promote cancer development.
Researchers at the Sanger Institute and their colleagues from The Institute of Cancer Research and the University of Cambridge tested all 18,108 possible DNA changes in the BAP1 gene by artificially altering the genetic code of human cells grown in a dish, a process known as ‘saturation genome editing’. They found that 5,665 of these changes were harmful and disrupted the protective effects of the protein3. Analysis of UK Biobank data confirmed that individuals carrying these harmful BAP1 variants are more than ten percent more likely to be diagnosed with cancer than the general population.
The team also found that people with harmful BAP1 variants had 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 or stop some cancers. Further analysis showed that harmful BAP1 variants and high IGF-1 levels were associated with poor outcomes in uveal melanoma patients, highlighting the potential of IGF-1 inhibitors in cancer therapy.
Notably, this technique profiles all possible BAP1 variants from diverse populations, not just variants prevalent in European clinical records, thereby helping to address the problem of under-representation of non-European populations in genetic studies.
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Dr Andrew Waters, first author of the study at the Wellcome Sanger Institute, said: “Previous methods of studying how variations affect function in genes have been on a very small scale, or have excluded important contexts that may contribute to their behaviour. Our approach provides a truer picture of gene behaviour, enabling larger and more complex studies of genetic variation4. This opens up new possibilities for understanding how these changes promote disease.”
Professor Clare Turnbull, clinical lead of the study, Professor of Translational Cancer Genetics at the Institute of Cancer Research in London and Consultant in Clinical Cancer Genetics at the Royal Marsden NHS Foundation, said: “This research means more accurate interpretation of genetic tests, earlier diagnosis and better outcomes for patients and their families.”
Dr David Adams, senior author of the study at the Wellcome Sanger Institute, said, “We want to ensure that life-saving genetic information is accessible and relevant to all people, regardless of their ancestry. We aim to apply this technology to a wide range of genes, potentially covering the entire human genome with the Atlas of Variant Effects in the next decade.” (ANI)
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