PT  - JOURNAL ARTICLE
AU  - Philip S. Robinson
AU  - Laura E. Thomas
AU  - Federico Abascal
AU  - Hyunchul Jung
AU  - Luke M.R. Harvey
AU  - Hannah D. West
AU  - Sigurgeir Olafsson
AU  - Bernard C. H. Lee
AU  - Tim H.H. Coorens
AU  - Henry Lee-Six
AU  - Laura Butlin
AU  - Nicola Lander
AU  - Mathijs A. Sanders
AU  - Stefanie V. Lensing
AU  - Simon J.A. Buczacki
AU  - Rogier ten Hoopen
AU  - Nicholas Coleman
AU  - Roxanne Brunton-Sim
AU  - Simon Rushbrook
AU  - Kourosh Saeb-Parsy
AU  - Fiona Lalloo
AU  - Peter J. Campbell
AU  - Iñigo Martincorena
AU  - Julian R. Sampson
AU  - Michael R. Stratton
TI  - Inherited <em>MUTYH</em> mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells
AID  - 10.1101/2021.10.20.465093
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.10.20.465093
4099  - http://biorxiv.org/content/early/2021/10/22/2021.10.20.465093.short
4100  - http://biorxiv.org/content/early/2021/10/22/2021.10.20.465093.full
AB  - 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 sequenced normal tissue DNAs from 10 individuals with MAP. Somatic base substitution mutation rates in intestinal epithelial cells were elevated 2 to 5-fold in all individuals, except for one showing a 33-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 were 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.SummaryCompeting Interest StatementP.J.C. is a founder, consultant, and stockholder of Mu Genomics Ltd.