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ToolsRobinson, Philip S., Thomas, Laura E., Abascal, Federico, Jung, Hyunchul, Harvey, Luke M.R., West, Hannah D., Olafsson, Sigurgeir, Lee, Bernard C.H., Coorens, Tim H.H., Lee-Six, Henry, Butlin, Laura, Lander, Nicola, Truscott, Rebekah, Sanders, Mathijs A., Lensing, Stefanie V., Buczacki, Simon J.A., ten Hoopen, Rogier, Coleman, Nicholas, Brunton-Sim, Roxanne, Rushbrook, Simon, Saeb-Parsy, Kourosh, Lalloo, Fiona, Campbell, Peter J., Martincorena, Iñigo, Sampson, Julian R. and Stratton, Michael R. (2022) Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells. Nature Communications, 13 (1). ISSN 2041-1723
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Abstract
Cellular DNA damage caused by reactive oxygen species is repaired by the base excision repair (BER) pathway which includes the DNA glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, the mechanistic progression from germline MUTYH mutations to MUTYH-Associated Polyposis (MAP) is incompletely understood. Here, we sequence normal tissue DNAs from 10 individuals with MAP. Somatic base substitution mutation rates in intestinal epithelial cells were elevated 2 to 4-fold in all individuals, except for one showing a 31-fold increase, and were also increased in other tissues. The increased mutation burdens were of multiple mutational signatures characterised by C > A changes. Different mutation rates and signatures between individuals are likely due to different MUTYH mutations or additional inherited mutations in other BER pathway genes. The elevated base substitution rate in normal cells likely accounts for the predisposition to neoplasia in MAP. Despite ubiquitously elevated mutation rates, individuals with MAP do not display overt evidence of premature ageing. Thus, accumulation of somatic mutations may not be sufficient to cause the global organismal functional decline of ageing.
| Item Type: | Article |
|---|---|
| Additional Information: | Data availability: Source data are provided with this paper. Raw DNA sequencing data are deposited in the European Genome-Phenome Archive (EGA) with accession codes: EGAD00001007958 and EGAD00001007997. To ensure the data is used for academic and research purposes, the DNA sequencing data are available via controlled access. Applications to access the data should be directed to the WTSI CGP Data access committee via the contact details listed at the above links. Indefinite access to the data will be made upon request. Further details of the access policy are available at https://ega-archive.org/submission. The cBioPortal MutationMapper database was accessed at: https://www.cbioportal.org/mutation_mapper?standaloneMutationMapperGeneTab=ATM. The COSMIC Cancer Gene Census is available to download at: https://cancer.sanger.ac.uk/census. There are no restrictions to accessing the MutationMapper or COSMIC databases. |
| Uncontrolled Keywords: | general chemistry,general biochemistry,genetics and molecular biology,general,general physics and astronomy ,/dk/atira/pure/subjectarea/asjc/1600/1600 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > School of Health Sciences Faculty of Medicine and Health Sciences > Norwich Medical School |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 02 Jul 2026 14:58 |
| Last Modified: | 02 Jul 2026 14:58 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/103606 |
| DOI: | 10.1038/s41467-022-31341-0 |
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