title: Diverse mechanisms of somatic structural variations in human cancer genomes.
abstract: Identification of somatic rearrangements in cancer genomes has accelerated through analysis of high-throughput sequencing data. However, characterization of complex structural alterations and their underlying mechanisms remains inadequate. Here, applying an algorithm to predict structural variations from short reads, we report a comprehensive catalog of somatic structural variations and the mechanisms generating them, using high-coverage whole-genome sequencing data from 140 patients across ten tumor types. We characterize the relative contributions of different types of rearrangements and their mutational mechanisms, find that ~20% of the somatic deletions are complex deletions formed by replication errors, and describe the differences between the mutational mechanisms in somatic and germline alterations. Importantly, we provide detailed reconstructions of the events responsible for loss of CDKN2A/B and gain of EGFR in glioblastoma, revealing that these alterations can result from multiple mechanisms even in a single genome and that both DNA double-strand breaks and replication errors drive somatic rearrangements.
authors.affiliation: Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lixing
authors.initials: L
authors.lastname: Yang
authors.forename: Lovelace J
authors.initials: LJ
authors.lastname: Luquette
authors.forename: Nils
authors.initials: N
authors.lastname: Gehlenborg
authors.forename: Ruibin
authors.initials: R
authors.lastname: Xi
authors.forename: Psalm S
authors.initials: PS
authors.lastname: Haseley
authors.forename: Chih-Heng
authors.initials: CH
authors.lastname: Hsieh
authors.forename: Chengsheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Ren
authors.forename: Alexei
authors.initials: A
authors.lastname: Protopopov
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Raju
authors.initials: R
authors.lastname: Kucherlapati
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Park
mesh_terms: D000465:Algorithms; D002869:Chromosome Aberrations; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005909:Glioblastoma / Q000235:genetics; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology