UK researchers have mapped the exact variants in a gene that dramatically increase a person’s risk of developing cancer, paving the way for targeted treatment across diverse populations.

Over 5,000 genetic variants that enable certain cancers to thrive were identified, along with a potential therapeutic target to treat or even prevent these cancers from developing.

Researchers from the Wellcome Sanger Institute, and their collaborators at The Institute of Cancer Research, London and the University of Cambridge assessed the health impact of all possible genetic changes in the ‘tumour protection’ gene, BAP1.

They found around a fifth of these possible changes were pathogenic, significantly increasing the risk of developing cancers of the eye, lung lining, brain, skin, and kidney.

The team also uncovered a link between certain disruptive BAP1 variants and higher levels of IGF-1, a hormone and growth factor. This discovery opens the door to developing new drugs that could inhibit these harmful effects, potentially slowing down or preventing the progression of certain cancers.

The findings, published in Nature Genetics, are freely available so that they can be immediately used by doctors to help diagnose patients and choose the most effective therapies for them.

Importantly, as all possible variants were assessed, the findings benefit individuals from diverse ethnic backgrounds, who have historically been underrepresented in genetics research.

Professor Clare Turnbull, clinical lead of the study, Professor of Translational Cancer Genetics at The Institute of Cancer Research, London, 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.”

Variants increase cancer risk by 10%

The BAP1 protein acts as a powerful tumour 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%, typically occurring around middle age.

The research team tested all 18,108 possible DNA changes in the BAP1 gene using ‘saturation genome editing’. They identified 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 10% more likely to be diagnosed with cancer than the general population.

IGF-1 inhibitors as cancer therapy

The team also discovered that people with harmful BAP1 variants 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.

Further 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.

Dr Andrew Waters, first author of the study at the Wellcome Sanger Institute, commented: “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 variation. This opens up new possibilities for understanding how these changes drive disease.”

Diana Spencer, Senior Digital Content Editor, DDW