Projects per year
Abstract
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.
Original language | English |
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Pages (from-to) | 666-675 |
Number of pages | 10 |
Journal | Genome Research |
Volume | 28 |
Issue number | 5 |
Early online date | 10 Apr 2018 |
DOIs | |
Publication status | Published - May 2018 |
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
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Dive into the research topics of 'Mutational signatures of DNA mismatch repair deficiency in C. elegans and human cancers'. Together they form a unique fingerprint.Projects
- 1 Finished
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Processing of Branched DNA Molecules During Cytokinesis, Uncovering New Mechanisms of Genome Maintenance
Gartner, A. (Investigator), Lilley, D. (Investigator) & Rouse, J. (Investigator)
Biotechnology and Biological Sciences Research Council
1/12/18 → 30/06/22
Project: Research
Profiles
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Gartner, Anton
- Molecular Cell and Developmental Biology - Associate Staff of Genetics
Person: Associate Staff