Tumors harbor mutations in numerous genes, each with diverse mutation types ranging from single nucleotide changes to larger DNA insertions or deletions. Traditional screening methods have lacked the ability to efficiently assess these mutations in their natural context. MIT scientists have introduced a novel approach using prime editing, a CRISPR-based genome-editing variant, to streamline mutation screening.

In a study published in Nature Biotechnology, the team utilized prime editing to screen over 1,000 mutations in the p53 tumor suppressor gene. This innovative technique, faster and more straightforward than existing methods, revealed previously underestimated harmful effects of certain p53 mutations.

The potential of this method extends beyond p53 to various cancer-related genes, offering insights into tumor development, progression, and treatment responses. By swiftly generating and testing thousands of cancer patient genotypes, researchers can identify sensitivities or resistances to specific therapies.

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“In one experiment, you can generate thousands of genotypes that are seen in cancer patients, and immediately test whether one or more of those genotypes are sensitive or resistant to any type of therapy that you’re interested in using,” says Francisco Sanchez-Rivera, senior author of the study.

This study was made possible by the versatility of prime editing in creating diverse cancer-associated mutations and addresses the limitations of earlier CRISPR technologies by enabling precise engineering of point mutations, insertions, and deletions crucial for studying cancer genetics.

The team's optimization of prime editing guide RNAs enhances editing efficiency by minimizing inaccuracies. By applying this technique to p53 mutations in lung adenocarcinoma cells, researchers uncovered previously overlooked effects of specific mutations on cell fitness.

The study's findings challenge prior assumptions about the impact of certain p53 mutations on cell growth, emphasizing the importance of studying mutations within their natural genetic context.