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.
%0 Journal Article
%1 Jaeger2013
%A Jäger, Natalie
%A Schlesner, Matthias
%A Jones, David T W.
%A Raffel, Simon
%A Mallm, Jan-Philipp
%A Junge, Kristin M.
%A Weichenhan, Dieter
%A Bauer, Tobias
%A Ishaque, Naveed
%A Kool, Marcel
%A Northcott, Paul A.
%A Korshunov, Andrey
%A Drews, Ruben M.
%A Koster, Jan
%A Versteeg, Rogier
%A Richter, Julia
%A Hummel, Michael
%A Mack, Stephen C.
%A Taylor, Michael D.
%A Witt, Hendrik
%A Swartman, Benedict
%A Schulte-Bockholt, Dietrich
%A Sultan, Marc
%A Yaspo, Marie-Laure
%A Lehrach, Hans
%A Hutter, Barbara
%A Brors, Benedikt
%A Wolf, Stephan
%A Plass, Christoph
%A Siebert, Reiner
%A Trumpp, Andreas
%A Rippe, Karsten
%A Lehmann, Irina
%A Lichter, Peter
%A Pfister, Stefan M.
%A Eils, Roland
%D 2013
%J Cell
%K Adult; Aged; Chromosome Chromosomes, DNA Female; Human, Humans; Inactivation Male; Medulloblastoma, Mutation; Myelodysplastic Neoplasms, Nucleotide; Phase; Polymorphism, Replication; S Single Syndromes, X X; genetics/pathology; genetics;
%N 3
%P 567--581
%R 10.1016/j.cell.2013.09.042
%T Hypermutation of the inactive X chromosome is a frequent event in cancer.
%U http://dx.doi.org/10.1016/j.cell.2013.09.042
%V 155
%X 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.
@article{Jaeger2013,
__markedentry = {[bbrors:6]},
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.},
added-at = {2015-04-09T12:36:21.000+0200},
author = {J{\"{a}}ger, Natalie and Schlesner, Matthias and Jones, David T W. and Raffel, Simon and Mallm, Jan-Philipp and Junge, Kristin M. and Weichenhan, Dieter and Bauer, Tobias and Ishaque, Naveed and Kool, Marcel and Northcott, Paul A. and Korshunov, Andrey and Drews, Ruben M. and Koster, Jan and Versteeg, Rogier and Richter, Julia and Hummel, Michael and Mack, Stephen C. and Taylor, Michael D. and Witt, Hendrik and Swartman, Benedict and Schulte-Bockholt, Dietrich and Sultan, Marc and Yaspo, Marie-Laure and Lehrach, Hans and Hutter, Barbara and Brors, Benedikt and Wolf, Stephan and Plass, Christoph and Siebert, Reiner and Trumpp, Andreas and Rippe, Karsten and Lehmann, Irina and Lichter, Peter and Pfister, Stefan M. and Eils, Roland},
biburl = {https://www.bibsonomy.org/bibtex/2d78a552ef7368fe754cb51b546e9f1e3/bbrors},
doi = {10.1016/j.cell.2013.09.042},
institution = {Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.},
interhash = {9a0d0edcfd4aa6405152c91228cf5457},
intrahash = {d78a552ef7368fe754cb51b546e9f1e3},
journal = {Cell},
keywords = {Adult; Aged; Chromosome Chromosomes, DNA Female; Human, Humans; Inactivation Male; Medulloblastoma, Mutation; Myelodysplastic Neoplasms, Nucleotide; Phase; Polymorphism, Replication; S Single Syndromes, X X; genetics/pathology; genetics;},
language = {eng},
medline-pst = {ppublish},
month = Oct,
number = 3,
owner = {bbrors},
pages = {567--581},
pii = {S0092-8674(13)01216-6},
pmid = {24139898},
timestamp = {2015-04-09T12:36:21.000+0200},
title = {Hypermutation of the inactive X chromosome is a frequent event in cancer.},
url = {http://dx.doi.org/10.1016/j.cell.2013.09.042},
volume = 155,
year = 2013
}