1. Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells
- Author
-
Inigo Martincorena, Hannah West, Philip S. Robinson, Federico Abascal, Hyunchul Jung, Laura Butlin, Nicola Lander, Laura E. Thomas, Roxanne Brunton-Sim, Rogier ten Hoopen, Tim H. H. Coorens, Michael R. Stratton, Henry Lee-Six, Simon M. Rushbrook, Kourosh Saeb-Parsy, Mathijs A. Sanders, Bernard C H Lee, Luke M. R. Harvey, Fiona Lalloo, Nicholas Coleman, Peter J. Campbell, Sigurgeir Olafsson, Simon J.A. Buczacki, Julian R. Sampson, and Stefanie V Lensing
- Subjects
Genetics ,Mutation rate ,Mutation ,Germline mutation ,MUTYH ,Somatic cell ,Point mutation ,medicine ,Base excision repair ,Biology ,medicine.disease_cause ,Germline - 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 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.Summary
- Published
- 2021