2013, Cell, Diverse Mechanisms of Somatic Structural Variations in Human Cancer Genomes

Diverse Mechanisms of Somatic Structural Variations in Human Cancer Genomes

• Lixing Yang¹, 
• Lovelace J. Luquette¹, 
• Nils Gehlenborg^1, 3, 
• Ruibin Xi^1, 4, 
• Psalm S. Haseley^1, 5, 
• Chih-Heng Hsieh⁶, 
• Chengsheng Zhang⁶, 
• Xiaojia Ren⁵, 
• Alexei Protopopov⁷, 
• Lynda Chin⁷, 
• Raju Kucherlapati^2, 5,
• Charles Lee^6, 8, 
• Peter J. Park^1, 5, 9,

Summary

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.

http://www.sciencedirect.com/science/article/pii/S0092867413004510

140 tumor-normal pairs , whole genome sequencing,

SV detection & mechanisms indetification,
impressive SV  case study