Using data from humans and worms, researchers at the European Bioinformatics Institute (EMBL-EBI), the University of Dundee and the Wellcome Sanger Institute have generated new insights into the mutational causes of cancer.
Previous research has shown that one of the first DNA repair pathways associated with an increased risk of cancer is DNA mismatch repair (MMR). A new study used the nematode worm Caenorhabditis elegans as a model system for studying MMR in greater detail. The study showed that data obtained from controlled experiments on the worm model held relevance for humans, helping researchers refine what they know about cancer.
That study—“Mutational Signatures of DNA Mismatch Repair Deficiency in C. elegans and Human Cancers”—was published Tuesday in Genome Research.
“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%),” the researchers wrote in the study. “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.”
Anton Gartner, Ph.D., principal investigator in the Centre for Gene Regulation and Expression at Dundee, said in a statement that the study was initiated by a member of his research team, Bettina Meier when she assessed the mutations that arise when C. elegans is defective for one specific DNA repair pathway. the process of studying how DNA is passed on was greatly accelerated, he said, since it only takes three days to propagate these worms from one generation to the next.
“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,” Dr. Gartner said.
That question was addressed by another research team member, Nadia Volkova, a Ph.D. student at EMBL-EBI. She 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. This suggests that the same mutational process operates in nematodes and humans,” Volkova stated. “Our approach allows us to find the exact profile of MMR deficiency and to understand more about what happens when DNA repair goes wrong.”
Cancer is caused by DNA mutations which 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.
As DNA repair is not perfect, it can leave certain mutations unrepaired or repair them incorrectly leading to changes in DNA. Understanding the these mutational processes is an important first step in identifying the causes of cancer and potential avenues for new treatments, the researchers concluded.
“The DNA mutations we see in cancer cells were caused by a yin and yang of DNA damage and repair,” said Moritz Gerstung, Ph.D., research group leader at EMBL-EBI. “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,” Dr. Gerstung added. “Unfortunately, there's no black box to help us.”