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Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair

DNA repair defects underlie many cancer syndromes. We tested whether de novo germline mutations (DNMs) are increased in families with germline defects in polymerase proofreading or base excision repair. A parent with a single germline POLE or POLD1 mutation, or biallelic MUTYH mutations, had 3-4 fol...

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Autores principales: Sherwood, Kitty, Ward, Joseph C., Soriano, Ignacio, Martin, Lynn, Campbell, Archie, Rahbari, Raheleh, Kafetzopoulos, Ioannis, Sproul, Duncan, Green, Andrew, Sampson, Julian R., Donaldson, Alan, Ong, Kai-Ren, Heinimann, Karl, Nielsen, Maartje, Thomas, Huw, Latchford, Andrew, Palles, Claire, Tomlinson, Ian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10279637/
https://www.ncbi.nlm.nih.gov/pubmed/37336879
http://dx.doi.org/10.1038/s41467-023-39248-0
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author Sherwood, Kitty
Ward, Joseph C.
Soriano, Ignacio
Martin, Lynn
Campbell, Archie
Rahbari, Raheleh
Kafetzopoulos, Ioannis
Sproul, Duncan
Green, Andrew
Sampson, Julian R.
Donaldson, Alan
Ong, Kai-Ren
Heinimann, Karl
Nielsen, Maartje
Thomas, Huw
Latchford, Andrew
Palles, Claire
Tomlinson, Ian
author_facet Sherwood, Kitty
Ward, Joseph C.
Soriano, Ignacio
Martin, Lynn
Campbell, Archie
Rahbari, Raheleh
Kafetzopoulos, Ioannis
Sproul, Duncan
Green, Andrew
Sampson, Julian R.
Donaldson, Alan
Ong, Kai-Ren
Heinimann, Karl
Nielsen, Maartje
Thomas, Huw
Latchford, Andrew
Palles, Claire
Tomlinson, Ian
author_sort Sherwood, Kitty
collection PubMed
description DNA repair defects underlie many cancer syndromes. We tested whether de novo germline mutations (DNMs) are increased in families with germline defects in polymerase proofreading or base excision repair. A parent with a single germline POLE or POLD1 mutation, or biallelic MUTYH mutations, had 3-4 fold increased DNMs over sex-matched controls. POLE had the largest effect. The DNMs carried mutational signatures of the appropriate DNA repair deficiency. No DNM increase occurred in offspring of MUTYH heterozygous parents. Parental DNA repair defects caused about 20–150 DNMs per child, additional to the ~60 found in controls, but almost all extra DNMs occurred in non-coding regions. No increase in post-zygotic mutations was detected, excepting a child with bi-allelic MUTYH mutations who was excluded from the main analysis; she had received chemotherapy and may have undergone oligoclonal haematopoiesis. Inherited DNA repair defects associated with base pair-level mutations increase DNMs, but phenotypic consequences appear unlikely.
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spelling pubmed-102796372023-06-21 Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair Sherwood, Kitty Ward, Joseph C. Soriano, Ignacio Martin, Lynn Campbell, Archie Rahbari, Raheleh Kafetzopoulos, Ioannis Sproul, Duncan Green, Andrew Sampson, Julian R. Donaldson, Alan Ong, Kai-Ren Heinimann, Karl Nielsen, Maartje Thomas, Huw Latchford, Andrew Palles, Claire Tomlinson, Ian Nat Commun Article DNA repair defects underlie many cancer syndromes. We tested whether de novo germline mutations (DNMs) are increased in families with germline defects in polymerase proofreading or base excision repair. A parent with a single germline POLE or POLD1 mutation, or biallelic MUTYH mutations, had 3-4 fold increased DNMs over sex-matched controls. POLE had the largest effect. The DNMs carried mutational signatures of the appropriate DNA repair deficiency. No DNM increase occurred in offspring of MUTYH heterozygous parents. Parental DNA repair defects caused about 20–150 DNMs per child, additional to the ~60 found in controls, but almost all extra DNMs occurred in non-coding regions. No increase in post-zygotic mutations was detected, excepting a child with bi-allelic MUTYH mutations who was excluded from the main analysis; she had received chemotherapy and may have undergone oligoclonal haematopoiesis. Inherited DNA repair defects associated with base pair-level mutations increase DNMs, but phenotypic consequences appear unlikely. Nature Publishing Group UK 2023-06-19 /pmc/articles/PMC10279637/ /pubmed/37336879 http://dx.doi.org/10.1038/s41467-023-39248-0 Text en © The Author(s) 2023, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Sherwood, Kitty
Ward, Joseph C.
Soriano, Ignacio
Martin, Lynn
Campbell, Archie
Rahbari, Raheleh
Kafetzopoulos, Ioannis
Sproul, Duncan
Green, Andrew
Sampson, Julian R.
Donaldson, Alan
Ong, Kai-Ren
Heinimann, Karl
Nielsen, Maartje
Thomas, Huw
Latchford, Andrew
Palles, Claire
Tomlinson, Ian
Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair
title Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair
title_full Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair
title_fullStr Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair
title_full_unstemmed Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair
title_short Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair
title_sort germline de novo mutations in families with mendelian cancer syndromes caused by defects in dna repair
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10279637/
https://www.ncbi.nlm.nih.gov/pubmed/37336879
http://dx.doi.org/10.1038/s41467-023-39248-0
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