Hypermutation 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

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.