Comprehensive long-span paired-end-tag mapping reveals characteristic patterns of structural variations in epithelial cancer genomes.

Axel M Hillmer
Fei Yao
Koichiro Inaki
Wah Heng Lee
Pramila N Ariyaratne
Audrey S M Teo
Xing Yi Woo
Zhenshui Zhang
Hao Zhao
Leena Ukil
Jieqi P Chen
Feng Zhu
Jimmy B Y So
Manuel Salto-Tellez
Wan Ting Poh
Kelson F B Zawack
Niranjan Nagarajan
Song Gao
Guoliang Li
Vikrant Kumar
Hui Ping J Lim
Yee Yen Sia
Chee Seng Chan
See Ting Leong
Say Chuan Neo
Poh Sum D Choi
Hervé Thoreau
Patrick B O Tan
Atif Shahab
Xiaoan Ruan
Jonas Bergh
Per Hall
Valère Cacheux-Rataboul
Chia-Lin Wei
Khay Guan Yeoh
Wing-Kin Sung
Guillaume Bourque
Edison T Liu
Yijun Ruan


Somatic genome rearrangements are thought to play important roles in cancer development. We optimized a long-span paired-end-tag (PET) sequencing approach using 10-Kb genomic DNA inserts to study human genome structural variations (SVs). The use of a 10-Kb insert size allows the identification of breakpoints within repetitive or homology-containing regions of a few kilobases in size and results in a higher physical coverage compared with small insert libraries with the same sequencing effort. We have applied this approach to comprehensively characterize the SVs of 15 cancer and two noncancer genomes and used a filtering approach to strongly enrich for somatic SVs in the cancer genomes. Our analyses revealed that most inversions, deletions, and insertions are germ-line SVs, whereas tandem duplications, unpaired inversions, interchromosomal translocations, and complex rearrangements are over-represented among somatic rearrangements in cancer genomes. We demonstrate that the quantitative and connective nature of DNA-PET data is precise in delineating the genealogy of complex rearrangement events, we observe signatures that are compatible with breakage-fusion-bridge cycles, and we discover that large duplications are among the initial rearrangements that trigger genome instability for extensive amplification in epithelial cancers.