XHypermutation of the inactive X chromosome is a frequent event in cancer

Natalie Jäger; Matthias Schlesner; David T.W. Jones; Simon Raffel; Jan Philipp Mallm; Kristin M. Junge; Dieter Weichenhan; Tobias Bauer; Naveed Ishaque; Marcel Kool; Paul A. Northcott; Andrey Korshunov; Ruben M. Drews; Jan Koster; Rogier Versteeg; Julia Richter; Michael Hummel; Stephen C. Mack; Michael D. Taylor; Hendrik Witt; Benedict Swartman; Dietrich Schulte-Bockholt; Marc Sultan; Marie Laure Yaspo; Hans Lehrach; Barbara Hutter; Benedikt Brors; Stephan Wolf; Christoph Plass; Reiner Siebert; Andreas Trumpp; Karsten Rippe; Irina Lehmann; Peter Lichter; Stefan M. Pfister; Roland Eils

doi:10.1016/j.cell.2013.09.042

XHypermutation of the inactive X chromosome is a frequent event in cancer

Natalie Jäger, Matthias Schlesner, David T.W. Jones, Simon Raffel, Jan Philipp Mallm, Kristin M. Junge, Dieter Weichenhan, Tobias Bauer, Naveed Ishaque, Marcel Kool, Paul A. Northcott, Andrey Korshunov, Ruben M. Drews, Jan Koster, Rogier Versteeg, Julia Richter, Michael Hummel, Stephen C. Mack, Michael D. Taylor, Hendrik WittBenedict Swartman, Dietrich Schulte-Bockholt, Marc Sultan, Marie Laure Yaspo, Hans Lehrach, Barbara Hutter, Benedikt Brors, Stephan Wolf, Christoph Plass, Reiner Siebert, Andreas Trumpp, Karsten Rippe, Irina Lehmann, Peter Lichter, Stefan M. Pfister, Roland Eils

Research output: Contribution to journal › Article › peer-review

65 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	567
Number of pages	1
Journal	Cell
Volume	155
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2013.09.042
Publication status	Published - 24 Oct 2013
Externally published	Yes

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Jäger, N., Schlesner, M., Jones, D. T. W., Raffel, S., Mallm, J. P., Junge, K. M., Weichenhan, D., Bauer, T., Ishaque, N., Kool, M., Northcott, P. A., Korshunov, A., Drews, R. M., Koster, J., Versteeg, R., Richter, J., Hummel, M., Mack, S. C., Taylor, M. D., ... Eils, R. (2013). XHypermutation of the inactive X chromosome is a frequent event in cancer. Cell, 155(3), 567. https://doi.org/10.1016/j.cell.2013.09.042

@article{a7947a6b9684449ba2b1082f0880e0d9,

title = "XHypermutation of the inactive X chromosome is a frequent event in cancer",

abstract = "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.",

author = "Natalie J{\"a}ger and Matthias Schlesner and Jones, {David T.W.} and Simon Raffel and Mallm, {Jan Philipp} and Junge, {Kristin M.} and Dieter Weichenhan and Tobias Bauer and Naveed Ishaque and Marcel Kool and Northcott, {Paul A.} and Andrey Korshunov and Drews, {Ruben M.} and Jan Koster and Rogier Versteeg and Julia Richter and Michael Hummel and Mack, {Stephen C.} and Taylor, {Michael D.} and Hendrik Witt and Benedict Swartman and Dietrich Schulte-Bockholt and Marc Sultan and Yaspo, {Marie Laure} and Hans Lehrach and Barbara Hutter and Benedikt Brors and Stephan Wolf and Christoph Plass and Reiner Siebert and Andreas Trumpp and Karsten Rippe and Irina Lehmann and Peter Lichter and Pfister, {Stefan M.} and Roland Eils",

note = "Funding Information: We would like to acknowledge the members of the PedBrain Tumor and MMML-Seq Project contributing to the ICGC. For technical support and expertise, we thank the DKFZ Genomics and Proteomics Core Facility, specifically Sabine Schmidt and Sasithorn Chotewutmontri. We acknowledge assistance provided by Hans-J{\"o}rg Warnatz for RNA sequencing and analysis at the Max Planck Institute for Molecular Genetics. We especially express our gratitude to Edith Heard for very helpful comments on our manuscript. This work was principally supported by the PedBrain Tumor Project and the MMML-Seq Project contributing to the ICGC, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants 01KU1201A, MedSys 0315416C and 01KU1002A to 01KU1002J). Additional support came from the German Cancer Research Center Heidelberg Center for Personalized Oncology (DKFZ-HIPO), the Max Planck Society, Genome Canada, and the Canadian Institute for Health Research (CIHR) with cofunding from Genome BC, Genome Quebec, CIHR-ICR (Institute for Cancer Research), and the Dietmar Hopp Foundation. ",

year = "2013",

month = oct,

day = "24",

doi = "10.1016/j.cell.2013.09.042",

language = "English",

volume = "155",

pages = "567",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "3",

}

Jäger, N, Schlesner, M, Jones, DTW, Raffel, S, Mallm, JP, Junge, KM, Weichenhan, D, Bauer, T, Ishaque, N, Kool, M, Northcott, PA, Korshunov, A, Drews, RM, Koster, J, Versteeg, R, Richter, J, Hummel, M, Mack, SC, Taylor, MD, Witt, H, Swartman, B, Schulte-Bockholt, D, Sultan, M, Yaspo, ML, Lehrach, H, Hutter, B, Brors, B, Wolf, S, Plass, C, Siebert, R, Trumpp, A, Rippe, K, Lehmann, I, Lichter, P, Pfister, SM & Eils, R 2013, 'XHypermutation of the inactive X chromosome is a frequent event in cancer', Cell, vol. 155, no. 3, pp. 567. https://doi.org/10.1016/j.cell.2013.09.042

TY - JOUR

T1 - XHypermutation of the inactive X chromosome is a frequent event in cancer

AU - Jäger, Natalie

AU - Schlesner, Matthias

AU - Jones, David T.W.

AU - Raffel, Simon

AU - Mallm, Jan Philipp

AU - Junge, Kristin M.

AU - Weichenhan, Dieter

AU - Bauer, Tobias

AU - Ishaque, Naveed

AU - Kool, Marcel

AU - Northcott, Paul A.

AU - Korshunov, Andrey

AU - Drews, Ruben M.

AU - Koster, Jan

AU - Versteeg, Rogier

AU - Richter, Julia

AU - Hummel, Michael

AU - Mack, Stephen C.

AU - Taylor, Michael D.

AU - Witt, Hendrik

AU - Swartman, Benedict

AU - Schulte-Bockholt, Dietrich

AU - Sultan, Marc

AU - Yaspo, Marie Laure

AU - Lehrach, Hans

AU - Hutter, Barbara

AU - Brors, Benedikt

AU - Wolf, Stephan

AU - Plass, Christoph

AU - Siebert, Reiner

AU - Trumpp, Andreas

AU - Rippe, Karsten

AU - Lehmann, Irina

AU - Lichter, Peter

AU - Pfister, Stefan M.

AU - Eils, Roland

N1 - Funding Information: We would like to acknowledge the members of the PedBrain Tumor and MMML-Seq Project contributing to the ICGC. For technical support and expertise, we thank the DKFZ Genomics and Proteomics Core Facility, specifically Sabine Schmidt and Sasithorn Chotewutmontri. We acknowledge assistance provided by Hans-Jörg Warnatz for RNA sequencing and analysis at the Max Planck Institute for Molecular Genetics. We especially express our gratitude to Edith Heard for very helpful comments on our manuscript. This work was principally supported by the PedBrain Tumor Project and the MMML-Seq Project contributing to the ICGC, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants 01KU1201A, MedSys 0315416C and 01KU1002A to 01KU1002J). Additional support came from the German Cancer Research Center Heidelberg Center for Personalized Oncology (DKFZ-HIPO), the Max Planck Society, Genome Canada, and the Canadian Institute for Health Research (CIHR) with cofunding from Genome BC, Genome Quebec, CIHR-ICR (Institute for Cancer Research), and the Dietmar Hopp Foundation.

PY - 2013/10/24

Y1 - 2013/10/24

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84886784734&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2013.09.042

DO - 10.1016/j.cell.2013.09.042

M3 - Article

C2 - 24139898

AN - SCOPUS:84886784734

SN - 0092-8674

VL - 155

SP - 567

JO - Cell

JF - Cell

IS - 3

ER -

XHypermutation of the inactive X chromosome is a frequent event in cancer

Abstract

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