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

Autor: Robinson PS; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, CB10 1SA, UK.; Department of Paediatrics, University of Cambridge, Cambridge, CB2 0QQ, UK., Thomas LE; Institute of Life Science, Swansea University, Swansea, SA28PP, UK., Abascal F; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, CB10 1SA, UK., Jung H; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, CB10 1SA, UK., Harvey LMR; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, CB10 1SA, UK., West HD; Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK., Olafsson S; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, CB10 1SA, UK., Lee BCH; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, CB10 1SA, UK.; Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory, Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong., Coorens THH; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, CB10 1SA, UK., Lee-Six H; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, CB10 1SA, UK., Butlin L; Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK., Lander N; Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK., Truscott R; Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK., Sanders MA; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, CB10 1SA, UK.; Department of Haematology, Erasmus University Medical Centre, 3015 CN, Rotterdam, The Netherlands., Lensing SV; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, CB10 1SA, UK., Buczacki SJA; Nuffield Department of Surgical Sciences, Medical Sciences Division, University of Oxford, Oxford, UK., Ten Hoopen R; Department of Oncology, University of Cambridge, Cambridge, UK., Coleman N; Department of Pathology, University of Cambridge, Cambridge, UK.; Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK., Brunton-Sim R; Norfolk and Norwich University Hospital, Norwich, UK., Rushbrook S; Norfolk and Norwich University Hospital, Norwich, UK.; Norwich Medical School, University of East Anglia, Norwich, UK., Saeb-Parsy K; Department of Surgery, University of Cambridge, Cambridge, UK.; Cambridge NIHR Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge, UK., Lalloo F; Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Oxford Road, Manchester, UK., Campbell PJ; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, CB10 1SA, UK., Martincorena I; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, CB10 1SA, UK., Sampson JR; Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK., Stratton MR; Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, CB10 1SA, UK. mrs@sanger.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Jul 08; Vol. 13 (1), pp. 3949. Date of Electronic Publication: 2022 Jul 08.
DOI: 10.1038/s41467-022-31341-0
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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