Scientists have mapped all the possible outcomes of mutations in tumor suppressor genes.

Researchers at the Francis Crick Institute have mapped all the possible consequences of alterations in tumour suppressor genes. VHLThis is the first step in a larger study that will unravel the consequences of tens of thousands of genetic mutations in cancer-related genes.

This VHL map could help clinicians determine which patients are at risk of developing kidney cancer or who may respond to certain drugs.

Genetic changes, or mutations, occur when one or more components of DNA are altered. VHL Genes Increases the risk of kidney cancerHowever, many people are diagnosed with “variants of unknown significance.” VHL And they don't know how this affects their cancer risk.

According to a study published today Nature GeneticsThe Crick Institute researchers used a new technique called saturation genome editing.¹ Track over 2,000 features VHL Mutation of human cells over time.

They measured how long each cell survived. VHL Variants are given a “functional score”; the lower the score, the more harmful the variant is.

largely VHL The mutations analysed did not affect cell survival, so people with these mutations may not be at high risk, but because other mutations have been shown for the first time to be defective, patients with these mutations may be able to undergo regular testing to reduce their cancer risk.

The most harmful mutations killed the cells. VHL The gene increased the activity of another gene SkinThis gene is necessary for cells to survive in low oxygen conditions, but too much HIF protein can cause tumors.

delete Skin From these cells VHL The mutation keeps the cell alive and prevents the harmful effects of VHL. HIF.

Belzutifan, a drug that blocks the HIF protein, works only in people with mutations that affect the amount of HIF in their cells. The scoring system developed by the Crick team is VHL Mutations that benefit from verzucifan treatment.

Finally, the researchers compared their scoring system to a public database of kidney cancer and found that their method could predict previously clinically identified cancer-causing variants with 100% accuracy.

Many people are told that they have a “mutation of unknown significance” in their genes. VHL Many people do not know how gene mutations affect cancer risk. Our mutation function score could be a clinically useful test to classify patients. In fact, patients with the lowest scores are VHL “People with these gene mutations tend to have the highest rates of kidney cancer. We are now working to apply this method to more genes, so we can bring this level of diagnostic accuracy to more people.”

Greg Findlay, Group Leader, Functional Genomics Laboratory, Francis Crick Institute

“By fine-tuning our saturation genome editing method, we've shown that with a relatively simple test we can identify what the genes are that are different,” said first author Megan Buckley, currently a PhD student at the University of Cambridge. VHL The effect of mutations on human cells. Surprisingly, many of the mutations that may be associated with cancer received neutral scores on the test, suggesting that the scoring system could provide patients in limbo with clarity about what their genes are. VHL What does diagnosis mean?”

The lab is now collaborating with the Cancer Dynamics Laboratory at the Crick Cancer Institute to track how well the functional scores can predict tumor growth and response to treatment in cancer patients. VHL Mutations. The researchers are also collaborating with the Wellcome Sanger Institute and the London Cancer Institute to map the effects of all mutations in 15 other cancer risk genes.

The research was carried out in collaboration with Zhenya Ivakine's laboratory at the Hospital for Sick Children in Toronto, Canada, the Crick Institute of Cancer Dynamics led by Samra Turajlic, and Athina Ganner and colleagues at the University of Freiburg, Germany. Funding was provided by the Francis Crick Institute, Cancer Research UK, VHL UK/Ireland, and the German Research Foundation.