The landscape of DNA mismatch repair failures in human cells

Failure in mismatch repair (MMR) is a common occurrence in cancer (e.g. 20% of colorectal cancer) and is associated with microsatellite instability (MSI). Mutation signature analysis of thousands of cancer genomes have revealed that there are at least four mutational signatures of MMR failures (in the COSMIC database, these are Signature 6, 15, 20 and 26). Moreover, they appear to be differentially distributed across the genome. This means that there is more than one way in which MMR can and does fail in human cancers. From this knowledge, we expect that besides the well-known cancer incidences of MLH1 promoter methylation, perturbations in other MMR genes are more common than currently appreciated. In addition, it is very likely that there are combinatorial effects (epistatic interactions) in the MMR pathway, including recruitment by chromatin modifiers, which may give rise to unexpected mutation signatures. We are planning to explore this phenomenon in a systematic manner and find the underlying mutational processes of each of the MMR related signatures. We thereby aim to possibly refine (or re-define) them and identify novel molecular targets for cancer therapy. We will make use of a combination of experimental and computational approaches, which we established previously but have not been used in this manner before. Our innovative approach is likely to become a changing paradigm in the field of molecular evolution and cancer mutagenesis.

Our DNA is constantly at risk of damage, which can lead to errors when cells divide. Fortunately, our bodies have a built-in repair system called Mismatch Repair (MMR) that fixes these mistakes, helping to maintain genetic stability. However, when this system doesn't work correctly-a condition known as MMR deficiency (MMRd)-errors accumulate, leading to an increased risk of cancer. In our study, we explored how the absence of MMR affects human cells by using advanced genetic tools to switch off this repair system in the lab. We observed a significant rise in DNA mutations and identified patterns known to be linked with MMRd. Interestingly, we also discovered a new mutation pattern that hadn't been connected to MMRd before. This pattern was linked to specific genetic variations and unique types of DNA changes, offering fresh insights into how genetic mutations can develop when MMR is not working. When we compared our lab findings with data from real human tumors, we noticed some important differences. This suggests that the way MMRd influences mutations depends on the biological environment, highlighting the complexity of cancer development. Our research also provided the first direct evidence that MMR is involved in fixing a specific type of DNA damage linked to the chemical modification of DNA bases, known as 5-methylcytosine deamination. This repair function had only been suspected before based on cancer genome studies. Overall, our findings improve our understanding of how MMRd contributes to cancer. These insights could eventually lead to better cancer prevention strategies, diagnostics, and treatments by targeting the underlying genetic mechanisms.