Researchers have created a detailed map illustrating the potential effects of alterations to a gene known as VHL, which plays a role in suppressing tumors. This marks the initial stage of a significant research project aimed at unraveling the ramifications of thousands of genetic variations in genes linked to cancer.
Scientists at the Francis Crick Institute have meticulously mapped out the various outcomes resulting from modifications to a tumor-suppressing gene known as VHL. This marks the beginning of an extensive research effort to decode the consequences of numerous genetic variations associated with cancer.
The map of VHL could assist healthcare providers in determining which patients may be susceptible to developing kidney cancer or could potentially benefit from certain medications.
Genetic alterations or mutations occur when there are changes in one or more components of DNA. Modifications, whether acquired or inherited, in the VHL gene can escalate the risk of kidney cancer. However, many individuals are diagnosed with ‘variants of unknown significance’ in VHL and are uncertain about the implications for their cancer risk.
In a study released today in Nature Genetics, researchers at the Crick utilized a novel technique called saturation genome editing1 to track the behavior of over 2,000 different VHL variants in human cells over a period of time.
They gauged the survival rate of cells with each specific VHL variant, assigning a ‘function score’ based on the outcomes: the lower the score, the more detrimental the variant.
The majority of the analyzed VHL variants showed no impact on cell survival, suggesting that individuals with these variants may not face a significantly heightened risk. Conversely, certain other variants were found to be defective for the first time, indicating that patients with these variants may warrant regular screening to mitigate their cancer risk.
The most harmful variants caused cell death. The team observed that the faulty VHL gene amplified the activity of another gene known as HIF. This gene is essential for cell survival in low-oxygen environments, yet excessive HIF protein levels can lead to tumor formation.
Eliminating HIF from cells with these VHL mutations preserved cell viability, underscoring the dependency of the negative effects of VHL on HIF.
Belzutifan, a medication that inhibits the HIF protein, is only effective for individuals with mutations affecting the HIF levels in cells. The scoring system established by the Crick team could pinpoint individuals with VHL mutations who would benefit from belzutifan treatment.
Finally, the researchers compared their scoring methodology with publicly accessible databases on kidney cancer and found that their approach accurately predicted cancer-causing variants previously identified in clinical settings with a 100% success rate.
Greg Findlay, Chief of the Genome Function Lab at the Crick, mentioned: “Many individuals are informed that they possess a ‘variant of unknown significance’ in the VHL gene and are left in the dark regarding its impact on their cancer risk. Our variant function score could serve as a valuable clinical tool to categorize patients. Indeed, our study reveals that individuals with the lowest scoring VHL variants tend to have a higher incidence of kidney cancer. We are actively working to extend this methodology to other genes to offer this level of diagnostic precision to a broader population.”
Megan Buckley, primary author and current PhD candidate at the University of Cambridge, remarked: “Through refining the saturation genome editing technique, we have shown that a relatively straightforward test can elucidate the effects of various VHL mutations on human cells. Surprisingly, numerous variants potentially linked to cancer received neutral scores in this examination, indicating that the scoring system could provide clarity to patients uncertain about the implications of their VHL diagnosis.”
The laboratory is presently collaborating with the Cancer Dynamics Lab at the Crick to monitor the accuracy of the function score in predicting tumor development and the response to treatment in patients with VHL mutations. Additionally, they are partnering with the Wellcome Sanger Institute and The Institute of Cancer Research, London to map out all variant effects in 15 other genes associated with cancer risk.
This study was conducted in partnership with Zhenya Ivakine’s lab at the Hospital for Sick Children in Toronto, Canada, the Crick’s Cancer Dynamics Lab supervised by Samra Turajlic, and Athina Ganner and colleagues at the University of Freiburg in Germany. Funding for this research was provided by the Francis Crick Institute, Cancer Research UK, VHL UK/Ireland, and the German Research Foundation.
