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New Insights into the Origins of Mutations in Cancer

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The link between cancer mutations and DNA repair mechanisms has been well established. However, the specific origins of the mutation in these essential pathways have remained enigmatic.

Now, researchers at the European Bioinformatics Institute (EMBL-EBI), the University of Dundee, and the Wellcome Sanger Institute have used human and worm data to explore the mutational causes of cancer.

Findings from this new study – published in Genome Research in an article entitled “Mutational Signatures of DNA Mismatch Repair Deficiency in C. elegans and Human Cancers” – shows that results from controlled experiments on this model organism – the nematode worm C. elegans – are relevant to humans, helping researchers refine what they know about cancer.

“Controlled experiments in model organisms can be used to mimic some of the processes thought to operate on cancer genomes and to establish their exact origins,” explained co-senior study investigator Moritz Gerstung, Ph.D., a research group leader at EMBL-EBI.

Cancer's DNA.jpg

Cancer is caused by DNA mutations that can be triggered by a range of factors, including UV radiation, certain chemicals, and smoking, but also errors occurring naturally during cell division. A cell recognizes most of these mutations and corrects them through multiple repair mechanisms to maintain genomic fidelity. However, DNA repair is not perfect and can leave certain mutations unrepaired or repaired incorrectly, leading to changes in the underlying DNA code. Understanding the footprints of these mutational processes is an important first step in identifying the causes of cancer and potential avenues for new treatments.

“The DNA mutations we see in cancer cells were caused by a yin and yang of DNA damage and repair,” explains Dr. Gerstung. “When we study a patient’s cancer genome, we’re looking at the final outcome of multiple mutational processes that often go on for decades before the disease manifests itself. The reconstruction of these processes and their contributions to cancer development is a bit like the forensic analysis of a plane crash site, trying to piece together what’s happened. Unfortunately, there’s no black box to help us.”

Previous research has shown that one of the first DNA repair pathways associated with an increased risk of cancer is DNA mismatch repair (MMR). The MMR proteins typically scan DNA postreplication for errors along the nascent strand. Genetic knockouts in this pathway have resulted in a 1000-fold increase in DNA mutations—attesting to the importance of this process to maintain genomic integrity. The current study uses Caenorhabditis elegans as a model system for studying MMR in more detail.

“Here, we use C. elegans genome sequencing of pms-2 and mlh-1 knockouts to reveal the mutational patterns linked to C. elegans MMR deficiency and their dependency on endogenous replication errors and errors caused by deletion of the polymerase ε subunit pole-4,” the authors wrote. “Signature extraction from 215 human colorectal and 289 gastric adenocarcinomas revealed three MMR-associated signatures, one of which closely resembles the C. elegans MMR spectrum and strongly discriminates microsatellite stable and unstable tumors (AUC = 98%). A characteristic difference between human and C. elegans MMR deficiency is the lack of elevated levels of NCG > NTG mutations in C. elegans, likely caused by the absence of cytosine (CpG) methylation in worms. The other two human MMR signatures may reflect the interaction between MMR deficiency and other mutagenic processes, but their exact cause remains unknown.”

“My team initiated this project by assessing the kinds of mutations that arise when C. elegans is defective for one specific DNA repair pathway,” noted co-senior study investigator Anton Gartner, Ph.D., principal investigator in the Centre for Gene Regulation and Expression at Dundee. “As it only takes three days to propagate these worms from one generation to the next, the process of studying how DNA is passed on is greatly expedited. DNA mismatch repair is propagated for many generations, and this allowed us to deduce a distinct mutational pattern. The big question was if the same type of mutagenesis also occurred in human cancer cells.”

To address this question, the EMBL-EBI team compared the C. elegans results with genetic data from 500 human cancer genomes.

“We found a resemblance between the most common signature associated with mutations in MMR genes in humans and the patterns found in nematode worms,” concluded study co-author Nadia Volkova, a doctoral candidate at EMBL-EBI. “This suggests that the same mutational process operates in nematodes and humans. Our approach allows us to find the exact profile of MMR deficiency and to understand more about what happens when DNA repair goes wrong.”

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