The researchers mapped the effects of every potential alteration in key cancer genes.

Francis Crick Institute researchers have mapped all the possible consequences of changes in a tumour-suppressor gene called VHL, the first step in a larger research effort to unravel the consequences of tens of thousands of genetic mutations in cancer-related genes.

This VHL map may help clinicians determine which patients are at risk of developing VHL. Kidney cancer Or it may be a reaction to certain medications.

Genetic changes, or mutations, occur when one or more components of DNA are altered. Mutations in the VHL gene, whether acquired or inherited, can increase the risk of kidney cancer. However, many people are diagnosed with a VHL “mutation of unknown significance” and do not know what it means for their cancer risk.

According to a study published today Nature GeneticsResearchers at the Crick Institute used a new technique called saturation genome editing to track the function of more than 2,000 VHL variants. Human cells over time.

The researchers measured the number of cells that survived with each VHL variant and gave them a “functional score” — the lower the score, the more harmful the variant.

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

The most damaging mutations killed the cells. The team found that the faulty VHL gene boosts the activity of another gene called HIF, which is needed for cells to survive in low-oxygen conditions, but too much HIF protein can cause tumors.

Removing HIF from cells harboring these VHL mutations allowed the cells to survive, demonstrating that the deleterious effects of VHL are dependent on HIF.

Verzutifan, a drug that inhibits the HIF protein, is only effective in people with mutations that affect the amount of HIF present in cells. The scoring system developed by the Click team can identify people with VHL mutations who would benefit from verzutifan 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 they have a 'mutation of unknown significance' in their VHL gene but don't know what that means for cancer risk,” said Greg Findlay, group leader in the Functional Genomics Laboratory at the Crick Institute. “Our mutation function score has the potential to be a clinically useful test for classifying patients.”

“Indeed, we find that patients with the lowest VHL mutation scores tend to have the highest rates of developing kidney cancer. We are now working to apply this method to more genes so that we can bring this level of diagnostic accuracy to more people.”

“By fine-tuning our saturation genome editing approach, we've shown that we can identify how different VHL mutations affect human cells with a relatively simple test,” said first author Megan Buckley, a PhD student at the University of Cambridge.

“Surprisingly, many mutations that may be associated with cancer scored neutrally on this test. Scoring System “This could provide clarity to patients who are in a state of limbo about what a VHL diagnosis means.”

The lab is currently collaborating with the Crick Institute's Cancer Dynamics Laboratory to track how well the functional score can predict tumour growth and response to treatment in patients with VHL mutations, and with the Wellcome Sanger Institute and the London Cancer Institute to map all gene mutations. Mutant Impact on risk of 15 types of cancer gene.