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

Bettina Meier, Nadezda V. Volkova, Ye Hong, Pieta Schofield, Peter J. Campbell, Moritz Gerstung, Anton Gartner

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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 languageEnglish
Pages (from-to)666-675
Number of pages10
JournalGenome Research
Volume28
Issue number5
Early online date10 Apr 2018
DOIs
Publication statusPublished - May 2018

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DNA Repair-Deficiency Disorders
DNA Mismatch Repair
Neoplasms
Genome
Cytosine
Causality
Microsatellite Repeats
Methylation
Area Under Curve
Stomach
Adenocarcinoma
Mutation
Turcot syndrome

Cite this

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title = "Mutational signatures of DNA mismatch repair deficiency in C. elegans and human cancers",
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.",
author = "Bettina Meier and Volkova, {Nadezda V.} and Ye Hong and Pieta Schofield and Campbell, {Peter J.} and Moritz Gerstung and Anton Gartner",
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Mutational signatures of DNA mismatch repair deficiency in C. elegans and human cancers. / Meier, Bettina; Volkova, Nadezda V.; Hong, Ye; Schofield, Pieta; Campbell, Peter J.; Gerstung, Moritz; Gartner, Anton.

In: Genome Research, Vol. 28, No. 5, 05.2018, p. 666-675.

Research output: Contribution to journalArticle

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AU - Meier, Bettina

AU - Volkova, Nadezda V.

AU - Hong, Ye

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AU - Gartner, Anton

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