Hypermutation of the Inactive X Chromosome Is a Frequent Event in Cancer

Mutation is a fundamental process in tumorigenesis. However, the degree to which the rate of somatic mutation varies across the human genome and the mechanistic basis underlying this variation remain to be fully elucidated. Here, we performed a cross-cancer comparison of 402 whole genomes comprising...

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Main Authors:	Jäger, Natalie, Schlesner, Matthias, Jones, David T.W., Raffel, Simon, Mallm, Jan-Philipp, Junge, Kristin M., Weichenhan, Dieter, Bauer, Tobias, Ishaque, Naveed, Kool, Marcel, Northcott, Paul A., Korshunov, Andrey, Drews, Ruben M., Koster, Jan, Versteeg, Rogier, Richter, Julia, Hummel, Michael, Mack, Stephen C., Taylor, Michael D., Witt, Hendrik, Swartman, Benedict, Schulte-Bockholt, Dietrich, Sultan, Marc, Yaspo, Marie-Laure, Lehrach, Hans, Hutter, Barbara, Brors, Benedikt, Wolf, Stephan, Plass, Christoph, Siebert, Reiner, Trumpp, Andreas, Rippe, Karsten, Lehmann, Irina, Lichter, Peter, Pfister, Stefan M., Eils, Roland
Format:	Online
Language:	English
Published:	Cell Press 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898475/

id	pubmed-3898475
recordtype	oai_dc
spelling	pubmed-38984752014-01-24 Hypermutation of the Inactive X Chromosome Is a Frequent Event in Cancer Jäger, Natalie Schlesner, Matthias Jones, David T.W. Raffel, Simon Mallm, Jan-Philipp Junge, Kristin M. Weichenhan, Dieter Bauer, Tobias Ishaque, Naveed Kool, Marcel Northcott, Paul A. Korshunov, Andrey Drews, Ruben M. Koster, Jan Versteeg, Rogier Richter, Julia Hummel, Michael Mack, Stephen C. Taylor, Michael D. Witt, Hendrik Swartman, Benedict Schulte-Bockholt, Dietrich Sultan, Marc Yaspo, Marie-Laure Lehrach, Hans Hutter, Barbara Brors, Benedikt Wolf, Stephan Plass, Christoph Siebert, Reiner Trumpp, Andreas Rippe, Karsten Lehmann, Irina Lichter, Peter Pfister, Stefan M. Eils, Roland Article Mutation is a fundamental process in tumorigenesis. However, the degree to which the rate of somatic mutation varies across the human genome and the mechanistic basis underlying this variation remain to be fully elucidated. Here, we performed a cross-cancer comparison of 402 whole genomes comprising a diverse set of childhood and adult tumors, including both solid and hematopoietic malignancies. Surprisingly, we found that the inactive X chromosome of many female cancer genomes accumulates on average twice and up to four times as many somatic mutations per megabase, as compared to the individual autosomes. Whole-genome sequencing of clonally expanded hematopoietic stem/progenitor cells (HSPCs) from healthy individuals and a premalignant myelodysplastic syndrome (MDS) sample revealed no X chromosome hypermutation. Our data suggest that hypermutation of the inactive X chromosome is an early and frequent feature of tumorigenesis resulting from DNA replication stress in aberrantly proliferating cells. Cell Press 2013-10-24 /pmc/articles/PMC3898475/ /pubmed/24139898 http://dx.doi.org/10.1016/j.cell.2013.09.042 Text en © 2013 ELL & Excerpta Medica. https://creativecommons.org/licenses/by-nc-nd/3.0/ Open Access under CC BY-NC-ND 3.0 (https://creativecommons.org/licenses/by-nc-nd/3.0/) license
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Jäger, Natalie Schlesner, Matthias Jones, David T.W. Raffel, Simon Mallm, Jan-Philipp Junge, Kristin M. Weichenhan, Dieter Bauer, Tobias Ishaque, Naveed Kool, Marcel Northcott, Paul A. Korshunov, Andrey Drews, Ruben M. Koster, Jan Versteeg, Rogier Richter, Julia Hummel, Michael Mack, Stephen C. Taylor, Michael D. Witt, Hendrik Swartman, Benedict Schulte-Bockholt, Dietrich Sultan, Marc Yaspo, Marie-Laure Lehrach, Hans Hutter, Barbara Brors, Benedikt Wolf, Stephan Plass, Christoph Siebert, Reiner Trumpp, Andreas Rippe, Karsten Lehmann, Irina Lichter, Peter Pfister, Stefan M. Eils, Roland
spellingShingle	Jäger, Natalie Schlesner, Matthias Jones, David T.W. Raffel, Simon Mallm, Jan-Philipp Junge, Kristin M. Weichenhan, Dieter Bauer, Tobias Ishaque, Naveed Kool, Marcel Northcott, Paul A. Korshunov, Andrey Drews, Ruben M. Koster, Jan Versteeg, Rogier Richter, Julia Hummel, Michael Mack, Stephen C. Taylor, Michael D. Witt, Hendrik Swartman, Benedict Schulte-Bockholt, Dietrich Sultan, Marc Yaspo, Marie-Laure Lehrach, Hans Hutter, Barbara Brors, Benedikt Wolf, Stephan Plass, Christoph Siebert, Reiner Trumpp, Andreas Rippe, Karsten Lehmann, Irina Lichter, Peter Pfister, Stefan M. Eils, Roland Hypermutation of the Inactive X Chromosome Is a Frequent Event in Cancer
author_facet	Jäger, Natalie Schlesner, Matthias Jones, David T.W. Raffel, Simon Mallm, Jan-Philipp Junge, Kristin M. Weichenhan, Dieter Bauer, Tobias Ishaque, Naveed Kool, Marcel Northcott, Paul A. Korshunov, Andrey Drews, Ruben M. Koster, Jan Versteeg, Rogier Richter, Julia Hummel, Michael Mack, Stephen C. Taylor, Michael D. Witt, Hendrik Swartman, Benedict Schulte-Bockholt, Dietrich Sultan, Marc Yaspo, Marie-Laure Lehrach, Hans Hutter, Barbara Brors, Benedikt Wolf, Stephan Plass, Christoph Siebert, Reiner Trumpp, Andreas Rippe, Karsten Lehmann, Irina Lichter, Peter Pfister, Stefan M. Eils, Roland
author_sort	Jäger, Natalie
title	Hypermutation of the Inactive X Chromosome Is a Frequent Event in Cancer
title_short	Hypermutation of the Inactive X Chromosome Is a Frequent Event in Cancer
title_full	Hypermutation of the Inactive X Chromosome Is a Frequent Event in Cancer
title_fullStr	Hypermutation of the Inactive X Chromosome Is a Frequent Event in Cancer
title_full_unstemmed	Hypermutation of the Inactive X Chromosome Is a Frequent Event in Cancer
title_sort	hypermutation of the inactive x chromosome is a frequent event in cancer
description	Mutation is a fundamental process in tumorigenesis. However, the degree to which the rate of somatic mutation varies across the human genome and the mechanistic basis underlying this variation remain to be fully elucidated. Here, we performed a cross-cancer comparison of 402 whole genomes comprising a diverse set of childhood and adult tumors, including both solid and hematopoietic malignancies. Surprisingly, we found that the inactive X chromosome of many female cancer genomes accumulates on average twice and up to four times as many somatic mutations per megabase, as compared to the individual autosomes. Whole-genome sequencing of clonally expanded hematopoietic stem/progenitor cells (HSPCs) from healthy individuals and a premalignant myelodysplastic syndrome (MDS) sample revealed no X chromosome hypermutation. Our data suggest that hypermutation of the inactive X chromosome is an early and frequent feature of tumorigenesis resulting from DNA replication stress in aberrantly proliferating cells.
publisher	Cell Press
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898475/
_version_	1612049997418725376

Hypermutation of the Inactive X Chromosome Is a Frequent Event in Cancer

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