Increased somatic mutation burdens in normal human cells due to defective DNA polymerases

Philip S. Robinson; Tim H. H. Coorens; Claire Palles; Emily Mitchell; Federico Abascal; Sigurgeir Olafsson; Bernard C. H. Lee; Andrew R. J. Lawson; Henry Lee-six; Luiza Moore; Mathijs A. Sanders; James Hewinson; Lynn Martin; Claudia M. A. Pinna; Sara Galavotti; Raheleh Rahbari; Peter J. Campbell; Iñigo Martincorena; Ian Tomlinson; Michael R. Stratton

doi:10.1038/s41588-021-00930-y

Increased somatic mutation burdens in normal human cells due to defective DNA polymerases

Philip S. Robinson, Tim H. H. Coorens, Claire Palles, Emily Mitchell, Federico Abascal, Sigurgeir Olafsson, Bernard C. H. Lee, Andrew R. J. Lawson, Henry Lee-six, Luiza Moore, Mathijs A. Sanders, James Hewinson, Lynn Martin, Claudia M. A. Pinna, Sara Galavotti, Raheleh Rahbari, Peter J. Campbell, Iñigo Martincorena, Ian Tomlinson, Michael R. Stratton

Cancer and Genomic Sciences

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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
Early online date	30 Sept 2021
DOIs	https://doi.org/10.1038/s41588-021-00930-y
Publication status	Published - Oct 2021

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Robinson, P. S., Coorens, T. H. H., Palles, C., Mitchell, E., Abascal, F., Olafsson, S., Lee, B. C. H., Lawson, A. R. J., Lee-six, H., Moore, L., Sanders, M. A., Hewinson, J., Martin, L., Pinna, C. M. A., Galavotti, S., Rahbari, R., Campbell, P. J., Martincorena, I., Tomlinson, I., & Stratton, M. R. (2021). Increased somatic mutation burdens in normal human cells due to defective DNA polymerases. Nature Genetics, 53(10), 1434–1442. Advance online publication. https://doi.org/10.1038/s41588-021-00930-y

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title = "Increased somatic mutation burdens in normal human cells due to defective DNA polymerases",

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.",

author = "Robinson, {Philip S.} and Coorens, {Tim H. H.} and Claire Palles and Emily Mitchell and Federico Abascal and Sigurgeir Olafsson and Lee, {Bernard C. H.} and Lawson, {Andrew R. J.} and Henry Lee-six and Luiza Moore and Sanders, {Mathijs A.} and James Hewinson and Lynn Martin and Pinna, {Claudia M. A.} and Sara Galavotti and Raheleh Rahbari and Campbell, {Peter J.} and I{\~n}igo Martincorena and Ian Tomlinson and Stratton, {Michael R.}",

year = "2021",

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doi = "10.1038/s41588-021-00930-y",

language = "English",

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Robinson, PS, Coorens, THH, Palles, C, Mitchell, E, Abascal, F, Olafsson, S, Lee, BCH, Lawson, ARJ, Lee-six, H, Moore, L, Sanders, MA, Hewinson, J, Martin, L, Pinna, CMA, Galavotti, S, Rahbari, R, Campbell, PJ, Martincorena, I, Tomlinson, I & Stratton, MR 2021, 'Increased somatic mutation burdens in normal human cells due to defective DNA polymerases', Nature Genetics, vol. 53, no. 10, pp. 1434–1442. https://doi.org/10.1038/s41588-021-00930-y

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T1 - Increased somatic mutation burdens in normal human cells due to defective DNA polymerases

AU - Robinson, Philip S.

AU - Coorens, Tim H. H.

AU - Palles, Claire

AU - Mitchell, Emily

AU - Abascal, Federico

AU - Olafsson, Sigurgeir

AU - Lee, Bernard C. H.

AU - Lawson, Andrew R. J.

AU - Lee-six, Henry

AU - Moore, Luiza

AU - Sanders, Mathijs A.

AU - Hewinson, James

AU - Martin, Lynn

AU - Pinna, Claudia M. A.

AU - Galavotti, Sara

AU - Rahbari, Raheleh

AU - Campbell, Peter J.

AU - Martincorena, Iñigo

AU - Tomlinson, Ian

AU - Stratton, Michael R.

PY - 2021/10

Y1 - 2021/10

N2 - 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.

AB - 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.

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DO - 10.1038/s41588-021-00930-y

M3 - Article

SN - 1061-4036

VL - 53

SP - 1434

EP - 1442

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

Increased somatic mutation burdens in normal human cells due to defective DNA polymerases

Abstract

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