Abstract
Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.
| Original language | English |
|---|---|
| Pages (from-to) | 1434-1442 |
| Number of pages | 9 |
| Journal | Nature Genetics |
| Volume | 53 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 30 Sept 2021 |
Bibliographical note
Funding Information:We thank the staff of Wellcome Sanger Institute Sample Logistics, Genotyping, Pulldown, Sequencing and Informatics facilities for their contribution, and L. O’Neill, Y. Hooks, S. Gamble, C. Latimer and K. Roberts for their support with sample management and laboratory work. We thank L. Humphreys and the Cancer Research UK Mutographs Grand Challenge team for their support with this study; T. Mitchell for advice regarding statistical analyses; M. Gerstung and H. Vöhringer for help with analysis, advice and discussions; and K. Allinson (Cambridge University Hospitals) for assistance with histopathological review. We thank K. Sherwood (Edinburgh Cancer Research Centre, IGMM, University of Edinburgh) and L. Chegwidden (Institute of Cancer and Genomic Sciences, University of Birmingham) for their assistance in obtaining samples. We thank the participants of the CORGI and CORGI 2.0 studies, local investigators and their teams, without whose support this work would not have been possible. We thank C. Brewer, P. Lidder and T. Pullen (Royal Cornwall Hospital Trust), A. Latchford, H. Thomas and R. Man (St Marks Hospital, London), M. Petmann and A. Andrews (Nottingham University Hospitals NHS Trust), J. East, C. Lahiff and H. Purnell (Oxford University Hospitals NHS Foundation Trust) and J. Rothwell, G. Evans and J. Hill (Manchester University NHS Foundation Trust). We thank the participants and local coordinators at TwinsUK. This work was supported by a Cancer Research UK Grand Challenge Award (no. C98/A24032) and the Wellcome Trust (no. 206194), a CR-UK Programme grant (no. C6199/A27327) and an ERC EVOCAN award. P.S.R. is supported by a Wellcome Clinical PhD fellowship. T.H.H.C. is supported by a Wellcome PhD Studentship. R.R. is funded by Cancer Research UK (no. C66259/A27114). The TwinsUK study receives support from the National Institute for Health Research-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. L.M. is funded by the Jean Shank/Pathological Society Intermediate Fellowship.
Publisher Copyright:
© 2021, The Author(s).
