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

• Published in: Genome research Vol. 28; no. 5; pp. 666 - 675
• Main Authors: Meier, Bettina, Volkova, Nadezda V., Hong, Ye, Schofield, Pieta, Campbell, Peter J., Gerstung, Moritz, Gartner, Anton
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.05.2018
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Animals; Base Sequence; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Colorectal Neoplasms - genetics; CpG islands; Cytosine; Deoxyribonucleic acid; DNA; DNA methylation; DNA Mismatch Repair; DNA Mutational Analysis - methods; DNA Polymerase II - deficiency; DNA Polymerase II - genetics; DNA repair; Genomes; Humans; Mismatch repair; Mismatch Repair Endonuclease PMS2 - deficiency; Mismatch Repair Endonuclease PMS2 - genetics; Mutation; MutL Protein Homolog 1 - deficiency; MutL Protein Homolog 1 - genetics; Poly-ADP-Ribose Binding Proteins - deficiency; Poly-ADP-Ribose Binding Proteins - genetics; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Tumors; Worms
• ISSN: 1088-9051; 1549-5469; 1549-5469
• 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 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 N C G > 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.