Scientists are mapping all the possible effects of changes in the key tumor suppressor gene

Researchers at the Francis Crick Institute have mapped all the possible outcomes of changes in a tumor-suppressing gene called VHLthe first step in a massive research effort to untangle the effects of tens of thousands of genetic variants in cancer-related genes.

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

Genetic changes or variations occur when one or more building blocks in DNA change. Both acquired and inherited variants in VHL gene may increase the risk of kidney cancer. But many people are diagnosed with “variations of unknown significance.” VHL and they don’t know what that means for their cancer risk.

In research published today in Genetics of Natureresearchers at Crick used a new method called saturation genome editing¹ to monitor the operation of more than 2,000 different VHL variations in human cells over time.

They counted how many cells survived with each VHL variant, which was then given a ‘function score’: the lower the score, the more harmful the variant.

Most of VHL The variants analyzed did not affect cell survival, suggesting that individuals with these variants may not have a significantly higher risk. However, other variants have been shown to be defective for the first time, meaning that patients with these variants can now be offered regular screening to reduce their cancer risk.

The most deleterious variants caused cell death. The team found that the defective VHL gene increased the activity of another gene called FOE. This gene is necessary to help cells survive low oxygen, but too much HIF protein can cause tumors.

Subtraction FOE from cells with them VHL mutations kept the cells alive, showing that the negative effects of VHL depend on FOE.

Belzutifan, a drug that blocks the HIF protein, only works for people with mutations that affect the amount of HIF present in cells. The scoring system developed by the Crick group could identify people with VHL mutations that would benefit from belzutifan treatment.

Finally, the researchers compared their scoring system to publicly available kidney cancer databases, finding that their method could predict cancer-causing variants previously identified in the clinic with 100 percent accuracy.

Many people are told they have a “variant of unknown significance” in the VHL gene and are in the dark about what it means for their cancer risk. Our function variant score could be a clinically useful test to categorize patients. In fact, we show that patients with the lowest scores VHL variants tend to show kidney cancer at the highest rate. We are now working to apply this method to more genes to bring this level of diagnostic accuracy to more people.”

Greg Findlay, Group Leader, Genome Function Laboratory, The Francis Crick Institute

Megan Buckley, first author and current PhD student at the University of Cambridge, said: “By fine-tuning the saturation genome editing method, we have shown that a relatively simple test can identify what different VHL they make mutations in human cells. Surprisingly, many variants potentially associated with cancer had neutral scores in this test, suggesting that the scoring system could bring clarity to patients in limbo. VHL diagnosis means’.

The lab is now working with the Cancer Dynamics Laboratory at the Crick to monitor how well the function score can predict tumor growth and response to treatment in patients with VHL mutations. They are also working with the Wellcome Sanger Institute and the London Institute for Cancer Research to map all effect variants in 15 other cancer risk genes.

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