Researchers at the University of Cambridge and the NIHR Cambridge Biomedical Research Centre have developed a novel algorithm, PRRDetect, designed to more accurately identify critical mutations in tumors. This advancement could significantly improve cancer treatment outcomes, particularly in the field of immunotherapy, by revealing specific vulnerabilities within individual tumors.

The research highlights the overlooked importance of small insertions and deletions (InDels) in cancer development. As the study team noted, “Despite their deleterious effects, small insertions and deletions (InDels) have received far less attention than substitutions.”

Using data from Genomics England’s 100,000 Genomes Project, the researchers created isogenic CRISPR-edited human cellular models that mimic postreplicative repair dysfunction (PRRd). These models featured targeted gene edits affecting DNA mismatch repair (MMR) and the replicative polymerases Pol ε and Pol δ.

Published in Nature Genetics, the study was led by senior author Dr. Serena Nik-Zainal, professor of genomic medicine and bioinformatics at the University of Cambridge and NIHR research professor. Dr. Nik-Zainal emphasized the growing accessibility of genomic sequencing, stating, “We are getting closer to the point where getting your tumor sequenced will be as routine as a scan or blood test.”

She further noted the importance of tools like PRRDetect in the clinical setting: “To use genomics most effectively in the clinic, we need tools that give us meaningful information about how a person’s tumor might respond to treatment. This is especially important in cancers where survival is poorer, like lung cancer and brain tumors.”

Cancers with impaired DNA repair mechanisms, the team observed, tend to respond more favorably to treatment. PRRDetect enables better identification of such cancers, potentially allowing physicians to tailor therapies more precisely to each patient.

The algorithm was developed by analyzing distinctive indel mutation patterns in tumors with DNA repair deficiencies. These patterns, identified from full DNA sequences, allowed the team to pinpoint tumors with PRRd, which are known to be more responsive to immunotherapy.

Dr. Nik-Zainal and her colleagues focused their analysis on cancers more likely to exhibit PRRd, including those of the bowel, brain, endometrium, skin, lung, bladder, and stomach. Genomic data for the study was sourced from the 100,000 Genomes Project, a groundbreaking initiative by Genomics England and NHS England that sequenced 100,000 genomes from approximately 85,000 NHS patients affected by cancer or rare diseases.

The study identified 37 distinct indel mutation patterns across the seven cancer types. Of these, 10 were linked to known carcinogenic factors such as smoking and UV exposure, while eight were associated with PRRd. The remaining 19 mutation patterns were previously unclassified and may be tied to currently unknown cancer-causing mechanisms.

By Impact Lab