More than 5000 high-risk cancer gene variants identified

Thousands of genetic variants have been identified that significantly increase the risk of developing certain cancers.

Researchers from the Institute of Cancer Research, London, collaborating with the Wellcome Sanger Institute, near Cambridge and the University of Cambridge, assessed the effects of 18,108 DNA changes in the BAP1 gene. BAP1 is a well-known tumour suppressor gene across multiple cancer types, and when mutated can encourage cancer growth and development. Now, over 5000 genetic variants of BAP1 have been identified that enable cancers of the eye, lung lining, brain, skin and kidney to thrive.

'Previous approaches for studying how variants affect function in genes have been on a very small scale, or exclude important contexts that may contribute to how they behave,' said Dr Andrew Waters, first author of the study from the Wellcome Sanger Institute. '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.'

The researchers created 18,108 unique BAP1 variants, using a process called 'saturation genome editing'. This process allowed the creation of all possible genetic variants of the gene, and their functions assessed. Publishing their findings in Nature Genetics, the researchers discovered 6196 genetic variants to have abnormal functions, of which, 5665 were harmful.

Using UK Biobank data, the researchers confirmed that people carrying harmful BAP1 variants are over ten percent more likely to be diagnosed with cancer than the general population. Yet, until now, it was not known which specific BAP1 variants encouraged cancer growth.

Furthermore, a link between certain harmful BAP1 variants and higher levels of IGF-1 were also discovered. IGF-1 is a hormone that manages the effects of growth hormone, which promotes the normal growth of bones and tissues and is associated with both cancer growth and brain development. The identification of this link may aid the development of drugs that could inhibit the harmful effects of the variants, potentially slowing down or preventing the progression of particular cancers.

The researchers have made their results freely available so that they can be used straight away by doctors to help diagnose patients and aid treatment choice.

Clinical lead of the study, Professor Clare Turnbull, from the Institute of Cancer Research, said: 'This research could mean more accurate interpretation of genetic tests, earlier diagnoses and improved outcomes for patients and their families.'

Furthermore, because all genetic variants were studied, the researchers hope their findings will help individuals from diverse ethnic backgrounds, who have historically been underrepresented in genetics research.