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An algorithm, PRRDetect, that more accurately points out key mutations to target in tumors was developed by researchers at the University of Cambridge and NIHR Cambridge Biomedical Research Centre. Knowing a tumor’s very specific vulnerabilities could improve outcomes, including with immunotherapy.
The team wrote, “Despite their deleterious effects, small insertions and deletions (InDels) have received far less attention than substitutions.”
They used data from Genomics England’s 100,000 Genomes Project to create isogenic CRISPR-edited human cellular models of postreplicative repair dysfunction (PRRd). These models include individual and combined gene edits of DNA mismatch repair (MMR) and replicative polymerases (Pol ε and Pol δ).
The algorithm, they believe, could help guide personalized cancer treatment.
Their paper appears in Nature Genetics, and the senior author of the study is Serena Nik-Zainal, MD, PhD, professor of genomic medicine and bioinformatics at the University of Cambridge and NIHR research professor.
Nik-Zainal said, “Genomic sequencing is now far faster and cheaper than ever before. We are getting closer to the point where getting your tumor sequenced will be as routine as a scan or blood test.
“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 faulty DNA repair are more likely to be treated successfully. PRRDetect helps us better identify those cancers and, as we sequence more and more cancers routinely in the clinic, it could ultimately help doctors better tailor treatments to individual patients.”
The research team looked for patterns in DNA created by so-called “indel” mutations, in which letters are inserted or deleted from the normal DNA sequence.
They found unusual patterns of indel mutations in cancers that had faulty DNA repair mechanisms. Using this information, they developed an algorithm called PRRDetect, which identifies tumors with PRRd from a full DNA sequence.
Such tumors are more sensitive to immunotherapy, and the scientists hope that the PRRd algorithm could act like a “metal detector” to allow detection of patients who are more likely to have successful treatment with immunotherapy.
Nik-Zainal and her team looked at cancers that have a higher proportion of tumors with PRRd. These include bowel, brain, endometrial, skin, lung, bladder, and stomach cancers. Whole genome sequences of these cancers were provided by the 100,000 Genomes Project—a pioneering study led by Genomics England and NHS England, which sequenced 100,000 genomes from around 85,000 NHS patients affected by rare diseases or cancer.
The study identified 37 different patterns of indel mutations across the seven cancer types included in this study. Ten of these patterns were already linked to known causes of cancer, such as smoking and exposure to UV light. Eight were linked to PRRd. The remaining 19 patterns were new and could be linked to causes of cancer that are not fully understood yet.
News & FeaturesArtificial intelligenceCRISPRDNA repairGenome sequencingImmunotherapyMutationPrecision medicineTumors
