Researchers at the Wellcome Sanger Institute, The Francis Crick Institute, and other collaborating institutions have made significant progress in cancer research. More than 5,000 genetic variants that enable certain cancers to thrive have been identified, along with a potential therapeutic target to treat or prevent these cancers from developing. This breakthrough paves the way for precision medicine approaches in cancer treatment.
A team of scientists at the Wellcome Sanger Institute, in collaboration with The Francis Crick Institute, London, and the University of Cambridge, assessed the health impact of all possible genetic changes in the “tumor protection” gene, BAP1. The study found around a fifth of these possible changes to be pathogenic, significantly increasing the risk of developing cancers of the eye, lung lining, brain, skin, and kidney.
The Francis Crick Institute researchers have also mapped all the possible outcomes of changes to a tumor-suppressing gene called VHL, marking the first step in a significant research endeavor to understand the outcomes of tens of thousands of genetic variations in genes associated with cancer. This research is fundamental in the quest to unravel the complexity of cancer genetics.
The study published in Nature Genetics underscores the critical role of identifying genetic variants underlying diseases and accurately quantifying their functional effects. The von Hippel-Lindau tumor suppressor (VHL) gene exemplifies the challenge of variant interpretation. This gene encodes an E3 ubiquitin ligase that regulates the cellular response to hypoxia and harbors germline pathogenic variants that predispose patients to tumors including clear cell renal cell carcinoma (ccRCC) and pheochromocytoma.
Optimizing and applying saturation genome editing to assay nearly all possible single-nucleotide variants (SNVs) across VHL’s coding sequence, the study provides essential insights. Function scores for 2,268 VHL SNVs identified a core set of pathogenic alleles driving ccRCC with perfect accuracy, informing differential risk across tumor types and revealing new mechanisms by which variants impact function. These results have immediate utility for classifying VHL variants encountered clinically and illustrate how precise functional measurements can resolve pleiotropic and dosage-dependent genotype-phenotype relationships across complete genes.
In conclusion, the identification of genetic variants enabling specific cancers and the detailed mapping of outcomes of changes to tumor-suppressing genes mark significant progress in cancer research. These breakthroughs hold promise for precision medicine approaches and understanding the complex interplay of genetics in cancer development and progression.
