title: Hypermutation 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.
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Jäger
authors.forename: Matthias
authors.initials: M
authors.lastname: Schlesner
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.forename: Simon
authors.initials: S
authors.lastname: Raffel
authors.forename: Jan-Philipp
authors.initials: JP
authors.lastname: Mallm
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Junge
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.forename: Tobias
authors.initials: T
authors.lastname: Bauer
authors.forename: Naveed
authors.initials: N
authors.lastname: Ishaque
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Ruben M
authors.initials: RM
authors.lastname: Drews
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
authors.forename: Julia
authors.initials: J
authors.lastname: Richter
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Mack
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Hendrik
authors.initials: H
authors.lastname: Witt
authors.forename: Benedict
authors.initials: B
authors.lastname: Swartman
authors.forename: Dietrich
authors.initials: D
authors.lastname: Schulte-Bockholt
authors.forename: Marc
authors.initials: M
authors.lastname: Sultan
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Yaspo
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.forename: Barbara
authors.initials: B
authors.lastname: Hutter
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.forename: Stephan
authors.initials: S
authors.lastname: Wolf
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.forename: Karsten
authors.initials: K
authors.lastname: Rippe
authors.forename: Irina
authors.initials: I
authors.lastname: Lehmann
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
mesh_terms: D000328:Adult; D000368:Aged; D041321:Chromosomes, Human, X; D004261:DNA Replication; D005260:Female; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000473:pathology; D009369:Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016196:S Phase; D049951:X Chromosome Inactivation