TY - JOUR
T1 - Diverse mechanisms of somatic structural variations in human cancer genomes
AU - Yang, Lixing
AU - Luquette, Lovelace J.
AU - Gehlenborg, Nils
AU - Xi, Ruibin
AU - Haseley, Psalm S.
AU - Hsieh, Chih Heng
AU - Zhang, Chengsheng
AU - Ren, Xiaojia
AU - Protopopov, Alexei
AU - Chin, Lynda
AU - Kucherlapati, Raju
AU - Lee, Charles
AU - Park, Peter J.
N1 - Funding Information:
This work was supported by grants from NIH (RC1HG005482 to P.J.P., U24CA144025 to R.K., UO1HG005209 and UO1HG005725 to C.L. and U24CA143845 to L.C.). We thank The Cancer Genome Atlas project for providing the whole-genome data, the Information Technology Department at Harvard Medical School for providing computational resources, and Michael Talkowski and members of the Park laboratory for a careful reading of the manuscript. L.C. is founder and/or consultant for AVEO, Metamark, Karyopharm, and Eden. R.K. is on the board of directors of AVEO, Metamark, Enlight, and KEW Group.
PY - 2013/5/9
Y1 - 2013/5/9
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2013.04.010
DO - 10.1016/j.cell.2013.04.010
M3 - Article
C2 - 23663786
AN - SCOPUS:84877722178
SN - 0092-8674
VL - 153
SP - 919
EP - 929
JO - Cell
JF - Cell
IS - 4
ER -