The MMRDetect clinical algorithm makes it possible to identify tumours that have ‘mismatch repair deficiencies’ and then improve the personalisation of cancer therapies to exploit those weaknesses.
The study, led by researchers from the University of Cambridge’s Department of Medical Genetics and MRC Cancer Unit, identified nine DNA repair genes that are critical guardians of the human genome from damage caused by oxygen and water, as well as errors during cell division.
The team used a genome editing technology, CRISPR-Cas9, to ‘knock out’ (make inoperative) these repair genes in healthy human stem cells. In doing so, they observed strong mutation patterns, or mutational signatures, which offer useful markers of those genes and the repair pathways they are involved in, failing.
The study, funded by Cancer Research UK and published in the journal Nature Cancer, suggests that these signatures of repair pathway defects are on-going and could therefore serve as crucial biomarkers in precision medicine.
Senior author, Dr Serena Nik-Zainal, a Cancer Research UK Advanced Clinician Scientist at Cambridge University’s MRC Cancer Unit (pictured), said: “When we knock out different DNA repair genes, we find a kind of fingerprint of that gene or pathway being erased. We can then use those fingerprints to figure out which repair pathways have stopped working in each person’s tumour, and what treatments should be used specifically to treat their cancer.”
The new computer algorithm, MMRDetect, uses the mutational signatures that were identified in the knock out experiments, and was trained on whole genome sequencing data from NHS cancer patients in the 100,000 Genomes Project, to identify tumours with ‘mismatch repair deficiency’ which makes them sensitive to checkpoint inhibitors, immunotherapies. Having developed the algorithm on tumours in this study, the plan now is to roll it out across all cancers picked up by Genomics England.
The breakthrough demonstrates the value of researchers working with the 100,000 Genomes Project, a pioneering national whole genome sequencing endeavour.
Reproduced courtesy of the University of Cambridge