Abstract
Researchers have identified the majority (94%) of MSH2 gene variants that could cause Lynch syndrome, a type of inherited colorectal cancer. Using deep mutational scanning, the researchers conducted a massively parallel screen in human cells to identify loss-of-function missense variants in the gene. MSH2 is a DNA mismatch repair factor, and variants are a major cause of Lynch syndrome.
Patients with a family history of Lynch Syndrome, also called hereditary non-polyposis colorectal cancer, are often recommended for screening, but the significance of nearly 90% of clinically observed missense variants is unknown.
Scientists at Michigan Medicine set out to measure the impact of as many mutations in MSH2 as possible. As described in the American Journal of Human Genetics, they used CRISPR-Cas technology to delete the normal copy of MSH2 from human cells and replaced it with a library of every possible mutation in the MSH2 gene. This created a mix of cells where each one carried a unique MSH2 mutation. Those cells were then treated with a drug known as 6-thioguanine, a chemotherapy that killed only the cells that had a functional variant of MSH2.
The idea was that the surviving cells are the ones without functioning MSH2–which are the ones with mutations that are most likely to be disease-causing. The team's hope is that, with other patient-specific information, some of these variants may be able to be reclassified, and it will be clearer which patients need to undergo more intense screening.
