Researchers have successfully pinpointed specific variants within a gene that significantly raise the risk of developing various types of cancer. This breakthrough could revolutionize early detection and targeted treatment for cancer across different population groups.
Scientists have identified over 5,000 genetic variants that play a crucial role in promoting certain cancers, revealing a potential target for therapeutic interventions to either treat or prevent the onset of these cancers.
Experts from the Wellcome Sanger Institute, in collaboration with researchers from The Institute of Cancer Research, London, and the University of Cambridge, examined the impact of all potential genetic alterations in the ‘tumour protection’ gene, BAP1. They discovered that approximately one-fifth of these alterations were harmful, significantly raising the risk of developing cancers affecting the eye, lung lining, brain, skin, and kidney.
The results of this study, published in the journal Nature Genetics, are readily accessible for physicians to use in diagnosing patients and selecting the most effective treatment options. Importantly, the inclusivity of assessing all potential variants benefits individuals from diverse ethnic backgrounds, a group often underrepresented in genetic research.
The research team also identified a correlation between specific detrimental variants in the BAP1 gene and increased levels of IGF-1, a hormone and growth factor. This breakthrough could pave the way for the development of new medications that target these harmful effects, potentially slowing down or even preventing the progression of certain cancers.
The BAP1 protein plays a crucial role as a powerful tumour suppressor in the body, offering protection against cancers affecting the eye, lung lining, brain, skin, and kidney. Inherited variants that disrupt this protein can elevate an individual’s lifetime risk of developing these cancers by up to 50%, typically manifesting around middle age.
Early detection of these variants through genetic screening can inform preventive measures, significantly enhance treatment efficacy, and improve the quality of life for those affected. Yet, until now, there has been limited knowledge concerning the specific genetic alterations in BAP1 to watch out for, especially concerning rare variants that lead to malfunction and cancer progression.
Researchers from the Sanger Institute, along with their partners from The Institute of Cancer Research and the University of Cambridge, conducted comprehensive testing on all 18,108 potential DNA alterations in the BAP1 gene, altering the genetic code of human cells in a lab setting through ‘saturation genome editing.’ Their research revealed that 5,665 of these alterations were detrimental, disrupting the protective effects of the protein. Analysis of UK Biobank data confirmed that individuals carrying these harmful BAP1 variants have over a 10% higher likelihood of being diagnosed with cancer compared to the general population.
The researchers also found that individuals with harmful BAP1 variants exhibit heightened levels of IGF-1 in their blood, a hormone associated with both cancer growth and brain development. Interestingly, even individuals without cancer showed elevated IGF-1 levels, suggesting that targeting IGF-1 could offer new treatment avenues to slow down or prevent certain cancers. Further analysis revealed that harmful BAP1 variants and increased IGF-1 levels were linked to adverse outcomes in uveal melanoma patients, underscoring the potential of IGF-1 inhibitors in cancer therapy.
Notably, this technique explores all potential BAP1 variants across varied populations, not limited to those commonly found in European clinical records, thereby contributing to addressing the underrepresentation of non-European populations in genetic studies.
Dr. Andrew Waters, the study’s lead author from the Wellcome Sanger Institute, highlighted the significance of their approach in providing a comprehensive understanding of gene behavior, paving the way for more extensive and intricate studies on genetic variations to elucidate disease mechanisms.
Professor Clare Turnbull, the study’s clinical lead, emphasized the potential impact of this research in enabling more precise interpretation of genetic tests, leading to earlier diagnoses and improved outcomes for patients and their families.
Dr. David Adams, the study’s senior author at the Wellcome Sanger Institute, expressed the team’s commitment to making vital genetic insights accessible and applicable to all individuals, irrespective of their ancestry. The goal is to expand this technique to a broader range of genes, with the aspiration of eventually covering the entire human genome within the next decade through the Atlas of Variant Effects project.
