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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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spelling 2022-10-25T16:38:35.1779691 v2 60437 2022-07-11 Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells 6f80a1638d852bd88d37afe3aeb2fb62 0000-0002-8621-5285 Laura Thomas Laura Thomas true false 2022-07-11 BMS 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. Journal Article Nature Communications 13 1 Springer Science and Business Media LLC 2041-1723 8 7 2022 2022-07-08 10.1038/s41467-022-31341-0 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 NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Another institution paid the OA fee 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. 2022-10-25T16:38:35.1779691 2022-07-11T09:52:42.7098262 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Philip S. Robinson 0000-0002-6237-7159 1 Laura Thomas 0000-0002-8621-5285 2 Federico Abascal 0000-0002-6201-1587 3 Hyunchul Jung 4 Luke M. R. Harvey 5 Hannah D. West 6 Sigurgeir Olafsson 7 Bernard C. H. Lee 8 Tim H. H. Coorens 0000-0002-5826-3554 9 Henry Lee-Six 0000-0003-4831-8088 10 Laura Butlin 0000-0003-2753-1883 11 Nicola Lander 12 Rebekah Truscott 13 Mathijs A. Sanders 14 Stefanie V. Lensing 15 Simon J. A. Buczacki 16 Rogier ten Hoopen 0000-0003-0655-9182 17 Nicholas Coleman 18 Roxanne Brunton-Sim 19 Simon Rushbrook 20 Kourosh Saeb-Parsy 0000-0002-0633-3696 21 Fiona Lalloo 22 Peter J. Campbell 23 Iñigo Martincorena 0000-0003-1122-4416 24 Julian R. Sampson 25 Michael R. Stratton 0000-0001-6035-153x 26 60437__24551__28f9bb8b54514a5ca026e4bbebab36b7.pdf 60437.pdf 2022-07-12T13:54:13.4361878 Output 1732582 application/pdf Version of Record true © The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License true eng http://creativecommons.org/licenses/by/4.0/
title Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells
spellingShingle Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells
Laura Thomas
title_short Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells
title_full Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells
title_fullStr Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells
title_full_unstemmed Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells
title_sort Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells
author_id_str_mv 6f80a1638d852bd88d37afe3aeb2fb62
author_id_fullname_str_mv 6f80a1638d852bd88d37afe3aeb2fb62_***_Laura Thomas
author Laura Thomas
author2 Philip S. Robinson
Laura Thomas
Federico Abascal
Hyunchul Jung
Luke M. R. Harvey
Hannah D. West
Sigurgeir Olafsson
Bernard C. H. Lee
Tim H. H. Coorens
Henry Lee-Six
Laura Butlin
Nicola Lander
Rebekah Truscott
Mathijs A. Sanders
Stefanie V. Lensing
Simon J. A. Buczacki
Rogier ten Hoopen
Nicholas Coleman
Roxanne Brunton-Sim
Simon Rushbrook
Kourosh Saeb-Parsy
Fiona Lalloo
Peter J. Campbell
Iñigo Martincorena
Julian R. Sampson
Michael R. Stratton
format Journal article
container_title Nature Communications
container_volume 13
container_issue 1
publishDate 2022
institution Swansea University
issn 2041-1723
doi_str_mv 10.1038/s41467-022-31341-0
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description 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.
published_date 2022-07-08T04:18:33Z
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score 11.037581

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