Genome research 2018 04 10() doi 10.1101/gr.226845.117
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 genome sequencing of and knockouts to reveal the mutational patterns linked to MMR deficiency and their dependency on endogenous replication errors and errors caused by deletion of the polymerase ε subunit Signature extraction from 215 human colorectal and 289 gastric adenocarcinomas revealed three MMR-associated signatures, one of which closely resembles the MMR spectrum and strongly discriminates microsatellite stable and unstable tumors (AUC = 98%). A characteristic difference between human and MMR deficiency is the lack of elevated levels of NG > NTG mutations in 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.