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Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells

Philip S. Robinson Orcid Logo, Laura Thomas Orcid Logo, Federico Abascal Orcid Logo, Hyunchul Jung, Luke M. R. Harvey, Hannah D. West, Sigurgeir Olafsson, Bernard C. H. Lee, Tim H. H. Coorens Orcid Logo, Henry Lee-Six Orcid Logo, Laura Butlin Orcid Logo, Nicola Lander, Rebekah Truscott, Mathijs A. Sanders, Stefanie V. Lensing, Simon J. A. Buczacki, Rogier ten Hoopen Orcid Logo, Nicholas Coleman, Roxanne Brunton-Sim, Simon Rushbrook, Kourosh Saeb-Parsy Orcid Logo, Fiona Lalloo, Peter J. Campbell, Iñigo Martincorena Orcid Logo, Julian R. Sampson, Michael R. Stratton Orcid Logo

Nature Communications, Volume: 13, Issue: 1

Swansea University Author: Laura Thomas Orcid Logo

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DOI (Published version): 10.1038/s41467-022-31341-0

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 MUTY...

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Published in: Nature Communications
ISSN: 2041-1723
Published: Springer Science and Business Media LLC 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa60437
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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 Description: 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.
College: Faculty of Medicine, Health and Life Sciences
Funders: This work was supported by the Wellcome Trust [206194]. P.S.R. is supported by a Wellcome Clinical PhD fellowship. Sample collection and research governance were supported by grants to Wales Gene Park from Health and Care Research Wales (H.C.R.W.). L.E.T. was supported by a postdoctoral Fellowship from HCRW and H.D.W. by a postdoctoral Fellowship from Ser Cymru.
Issue: 1

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