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Genome Res. 2018 May;28(5):666-675. doi: 10.1101/gr.226845.117. Epub 2018 Apr 10.

Mutational signatures of DNA mismatch repair deficiency in C. elegans and human cancers.

Author information

Centre for Gene Regulation and Expression, University of Dundee, Dundee DD1 5EH, United Kingdom.
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton CB10 1SD, United Kingdom.
Division of Computational Biology, University of Dundee, Dundee DD1 5EH, United Kingdom.
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom.
Department of Haematology, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
Department of Haematology, Addenbrooke's Hospital, Cambridge CB2 0XY, United Kingdom.
Contributed equally


Throughout their lifetime, cells are subject to extrinsic and intrinsic mutational processes leaving behind characteristic signatures in the genome. DNA mismatch repair (MMR) deficiency leads to hypermutation and is found in different cancer types. Although it is possible to associate mutational signatures extracted from human cancers with possible mutational processes, the exact causation is often unknown. 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 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. In summary, combining information from genetically defined models and cancer samples allows for better aligning mutational signatures to causal mutagenic processes.

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