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

Philip S. Robinson, Laura E. 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 Hoopen, Nicholas Coleman, Roxanne Brunton-Sim, Simon Rushbrook, Kourosh Saeb-Parsy, Fiona Lalloo, Peter J. Campbell, Iñigo Martincorena, Julian R. Sampson and Michael R. Stratton ()
Additional contact information
Philip S. Robinson: Wellcome Sanger Institute
Laura E. Thomas: Swansea University
Federico Abascal: Wellcome Sanger Institute
Hyunchul Jung: Wellcome Sanger Institute
Luke M. R. Harvey: Wellcome Sanger Institute
Hannah D. West: Cardiff University School of Medicine
Sigurgeir Olafsson: Wellcome Sanger Institute
Bernard C. H. Lee: Wellcome Sanger Institute
Tim H. H. Coorens: Wellcome Sanger Institute
Henry Lee-Six: Wellcome Sanger Institute
Laura Butlin: Cardiff University School of Medicine
Nicola Lander: Cardiff University School of Medicine
Rebekah Truscott: Cardiff University School of Medicine
Mathijs A. Sanders: Wellcome Sanger Institute
Stefanie V. Lensing: Wellcome Sanger Institute
Simon J. A. Buczacki: University of Oxford
Rogier Hoopen: University of Cambridge
Nicholas Coleman: University of Cambridge
Roxanne Brunton-Sim: Norfolk and Norwich University Hospital
Simon Rushbrook: Norfolk and Norwich University Hospital
Kourosh Saeb-Parsy: University of Cambridge
Fiona Lalloo: Saint Mary’s Hospital
Peter J. Campbell: Wellcome Sanger Institute
Iñigo Martincorena: Wellcome Sanger Institute
Julian R. Sampson: Cardiff University School of Medicine
Michael R. Stratton: Wellcome Sanger Institute

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31341-0

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