Scientists at the Francis Crick Institute have mapped all possible outcomes of changes to a tumor-suppressing gene called VHL, as the first step in a massive research project to unravel the consequences of tens of thousands of genetic variations in genes linked to cancer.
Clinicians may find it easier to identify patients having a higher risk of kidney cancer or react better to a particular medication by using this VHL map.
A change in one or more DNA building blocks results in genetic variations or changes. Variants in the VHL gene that are acquired or inherited can raise the risk of kidney cancer. However, many individuals receive a diagnosis of "variants of unknown significance" in VHL without understanding the implications for their risk of cancer.
Researchers at the Crick used a novel technique called saturation genome editing to monitor the function of more than 2,000 distinct VHL variants in human cells over time. The study was published in Nature Genetics.
Each VHL variant was assigned a "function score" based on the number of cells that survived; the lower the score, the more dangerous the variant.
The majority of the VHL variants that were examined had no effect on the cells' ability to survive, indicating that carriers of these variants might not be at appreciably increased risk. Some variants, on the other hand, were discovered to be defective for the first time, which means that patients who have these variants may now be offered routine screening to lower their risk of cancer.
The cells died in the most dangerous versions. The researchers discovered that the defective VHL gene elevated the activity of the HIF gene. While an excess of HIF protein can result in tumors, this gene is necessary for cells to survive in low oxygen environments.
The cells with these VHL mutations were able to survive when HIF was removed, demonstrating that HIF is necessary for the harmful effects of VHL.
Only those with mutations affecting the quantity of HIF present in cells can benefit from belzutifan, a medication that inhibits the HIF protein. Belzutifan treatment could be beneficial for individuals with VHL mutations according to the Crick team's scoring system.
When the researchers finally compared their scoring system to databases on kidney cancer that were made available to the public, they discovered that their approach could 100% accurately predict cancer-causing variants that had previously been found in clinics.
Lots of people are told they have a ‘variant of unknown significance’ in the VHL gene and they’re in the dark about what that means for their cancer risk. Our variant function score could be a clinically useful test to categorize patients. In fact, we show that patients with the lowest scoring VHL variants tend to get kidney cancer at the highest rate. We are now working to apply this method to more genes to bring this level of diagnostic precision to more people.”
Greg Findlay, Group Leader, Genome Function Laboratory, Francis Crick Institute
Megan Buckley, Study First Author and Current Ph.D. Student at the University of Cambridge, said: “By fine-tuning the saturation genome editing method, we’ve shown that a relatively simple test can identify what different VHL mutations do in human cells. Surprisingly, lots of variants potentially linked to cancer had neutral scores in this test, suggesting that the scoring system could bring clarity to patients in limbo about what their VHL diagnosis means.”
To monitor how well the function score can forecast tumor growth and treatment response in patients with VHL mutations, the lab is currently collaborating with the Cancer Dynamics Laboratory at the Crick.
In order to map all variant effects across 15 additional cancer risk genes, they are also collaborating with the Wellcome Sanger Institute and The Institute of Cancer Research, London.
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