Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells
Robinson PS., Thomas LE., Abascal F., Jung H., Harvey LMR., West HD., Olafsson S., Lee BCH., Coorens THH., Lee-Six H., Butlin L., Lander N., Truscott R., Sanders MA., Lensing SV., Buczacki SJA., ten Hoopen R., Coleman N., Brunton-Sim R., Rushbrook S., Saeb-Parsy K., Lalloo F., Campbell PJ., Martincorena I., Sampson JR., Stratton MR.
AbstractCellular 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.