5,000 genetic variants that enable cancer to thrive identified by Wellcome Sanger Institute, ICR and University of Cambridge

More than 5,000 genetic variants that enable certain cancers to thrive have been identified - along with a potential therapeutic target to treat or even prevent the tumours from developing.

A study of all the possible genetic changes to the ‘tumour protection’ gene, BAP1, found a fifth of a them were pathogenic, significantly increasing the risk of developing cancers of the eye, lung lining, brain, skin, and kidney.

The researchers from the Wellcome Sanger Institute, with collaborators at The Institute of Cancer Research in London and the University of Cambridge, also uncovered a link between certain disruptive BAP1 variants and higher levels of IGF-1, a hormone and growth factor. This could help the development of new drugs to inhibit the harmful effects, potentially slowing down or preventing the progression of certain cancers.

The BAP1 protein is a powerful tumour suppressor, protecting against cancers of the eye, lung lining, brain, skin, and kidney, but inherited variants that disrupt it can increase a person's lifetime risk of developing these cancers by up to 50 per cent, typically occurring around middle age.

Detecting these variants early through genetic screening would guide preventative measures, greatly enhance the effectiveness of treatment effectiveness and improve quality of life for individuals affected.

But until now, there has been limited understanding of which specific genetic changes in BAP1 to look out for - especially those rare variants that cause it to malfunction and fuel cancer growth.

Some 18,108 DNA changes in the BAP1 gene were studied by artificially altering the genetic code of human cells grown in a dish in a process known as ‘saturation genome editing’. Of these, 5,665 were harmful and disrupted the protein’s protective effects.

Analysis of UK Biobank data confirmed individuals with these harmful BAP1 variants are more than 10 per cent more likely to be diagnosed with cancer than the general population.

People with harmful BAP1 variants also have elevated levels of IGF-1 in their blood, they found. This hormone is linked to both cancer growth and brain development.

Even individuals with these variants but without cancer showed these elevated levels, suggesting that IGF-1 could be a target for new treatments to slow down or prevent certain cancers.

Analysis showed 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.

Dr Andrew Waters, first author of the study at the Sanger Institute, said: “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 behaviour, enabling larger and more complex studies of genetic variation4. This opens up new possibilities for understanding how these changes drive disease.”

Prof Clare Turnbull, clinical lead of the study, professor of translational cancer genetics at The Institute of Cancer Research and consultant in clinical cancer genetics at 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, senior author of the study at the 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.”

The findings were published in Nature Genetics and have been made freely available to help doctors diagnose patients and choose the most effective therapies. The findings could benefit people from diverse ethnic backgrounds - historically underrepresented in genetics research - since all variants were assessed.