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Elsevier, Cell, 3(155), p. 567-581, 2013

DOI: 10.1016/j.cell.2013.09.042

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

Journal article published in 2013 by Natalie Jäger, Matthias Schlesner ORCID, David T. W. Jones, Simon Raffel ORCID, Jan-Philipp Mallm, Kristin M. Junge, Dieter Weichenhan, Tobias Bauer, Naveed Ishaque ORCID, Marcel Kool, Paul A. Northcott ORCID, Andrey Korshunov, Ruben M. Drews ORCID, Jan Koster, Rogier Versteeg and other authors.
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This paper is available in a repository.

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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.