Diverse Mechanisms of Somatic Structural Variations in Human Cancer Genomes
A partir de données de séquençage du génome entier portant sur 140 patients atteints de cancer, cette étude dresse un catalogue des variations structurales somatiques et analyse les différences entre les mécanismes associés aux altérations somatiques et aux altérations de la lignée germinale
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. "A cross-tumor analysis of whole-genome sequencing data from 140 patients "An algorithm that identifies complex deletions from short-read data "A comprehensive spectrum of structural variation types and mechanisms reported "Main driving forces of cancer genome rearrangements are proposed An algorithm that predicts structural variants from short-read sequencing reveals a comprehensive catalog of the nature and extent of genomic rearrangement across a large variety of cancer genomes.