Comprehensive Analysis Identifies Risk Factors for Multiple Cancers

Scientists have discovered over 5,000 genetic variations linked to specific cancers and identified potential therapeutic targets that could be used to treat or halt the growth of these cancers.

Researchers at the University of Cambridge, The Institute of Cancer Research in London, and the Wellcome Sanger Institute evaluated the potential health effects of all genetic variations in the "tumor protection" gene, BAP1. They discovered that about 25% of these potential alterations were harmful, greatly raising the chance of developing cancers in the kidney, brain, skin, eyes, and linings of the lungs.

The results, which were published in Nature Genetics, are openly accessible so that medical professionals can use them right away to diagnose patients and determine the best courses of treatment for them. Crucially, because every potential variation was evaluated, people from a variety of ethnic backgrounds - who have traditionally been underrepresented in genetics research - benefit from the findings.

The researchers also discovered a connection between elevated levels of the hormone and growth factor IGF-1 and specific disruptive BAP1 variants. The development of novel medications that block these detrimental effects may be made possible by this discovery, potentially slowing or stopping the spread of some cancers.

In the body, the BAP1 protein functions as a potent tumor suppressor, guarding against cancers of the kidney, brain, skin, eye, and lung lining. A person's lifetime risk of acquiring these cancers can rise by up to 50% due to inherited variants that disrupt the protein; these mutations usually manifest around middle age.

Early genetic screening detection of these variants can direct preventative measures, significantly increase treatment efficacy, and enhance the quality of life for those who are affected. Nevertheless, little is known about the precise genetic alterations in BAP1 to be on the lookout for up until now, particularly for uncommon variants that cause it to malfunction and promote the growth of cancer.

Through a technique known as "saturation genome editing," researchers from the Sanger Institute, in collaboration with The Institute of Cancer Research and the University of Cambridge, examined every 18,108 potential DNA alterations in the BAP1 gene by manipulating the genetic code of human cells cultured in a dish.

They determined that 5,665 of these alterations were detrimental and interfered with the protective functions of the protein. According to an analysis of UK Biobank data, people who have these dangerous BAP1 variants have a diagnosis of cancer over ten percent higher than the general population.

The researchers also found that individuals with deleterious BAP1 variants had higher blood levels of IGF-1, a hormone connected to the development of the brain and the growth of cancer. These elevated levels were even seen in non-cancerous individuals, indicating that IGF-1 may be a target for novel treatments aimed at delaying or preventing specific cancers.

Subsequent examination demonstrated that detrimental BAP1 mutations and elevated IGF-1 levels were associated with unfavorable results in uveal melanoma patients, underscoring the possibility of employing IGF-1 inhibitors in cancer treatment.

Interestingly, the method addresses the underrepresentation of non-European populations in genetic studies by profiling all potential BAP1 variants from diverse populations, not just those common in European clinical records.

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. Our approach provides a true picture of gene behavior, enabling larger and more complex studies of genetic variation4. This opens up new possibilities for understanding how these changes drive disease.”

Dr. Andrew Waters, Study First Author, Wellcome Sanger Institute

Clare Turnbull, Professor, Study Clinical Lead and Consultant, Translational Cancer Genetics, The Institute of Cancer Research, London, Clinical Cancer Genetics, The Royal Marsden NHS Foundation, said: “This research could mean more accurate interpretation of genetic tests, earlier diagnoses and improved outcomes for patients and their families.”

Dr. David Adams, Study Senior Author, Wellcome Sanger Institute, said, “We want to ensure that life-saving genetic insights are accessible and relevant to all people, regardless of their ancestry. 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.”