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An Integrative Framework for Detecting Structural Variations in Cancer Genomes

Jesse R. Dixon, Jie Xu, Vishnu Dileep, Ye Zhan, Fan Song, Victoria T. Le, Galip Gürkan Yardimci, Abhijit Chakraborty, Darrin V. Bann, Yanli Wang, Royden Clark, Lijun Zhang, Hongbo Yang, Tingting Liu, Sriranga Iyyanki, Lin An, Christopher Pool, Takayo Sasaki, Juan Carlos Rivera Mulia, Hakan Ozadam, Bryan R. Lajoie, Rajinder Kaul, Michael Buckley, Kristen Lee, Morgan Diegel, Dubravka Pezic, Christina Ernst, Suzana Hadjur, Duncan T. Odom, John A. Stamatoyannopoulos, James R. Broach, Ross Hardison, Ferhat Ay, William Stafford Noble, Job Dekker, David M. Gilbert, Feng Yue
doi: https://doi.org/10.1101/119651
Jesse R. Dixon
1Salk Institute for Biological Studies, 10010 N Torrey Pines Rd. La Jolla, CA 92130, USA.
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  • For correspondence: fyue@hmc.psu.edu gilbert@bio.fsu.edu Job.Dekker@umassmed.edu wnoble@uw.edu ferhatay@lji.org jedixon@salk.edu
Jie Xu
2Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA.
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Vishnu Dileep
3Department of Biological Science, 319 Stadium Drive, Florida State University, Tallahassee, Florida 32306-4295, USA.
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Ye Zhan
4Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
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Fan Song
5Bioinformatics and Genomics Program, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
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Victoria T. Le
1Salk Institute for Biological Studies, 10010 N Torrey Pines Rd. La Jolla, CA 92130, USA.
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Galip Gürkan Yardimci
6Department of Genome Sciences, University of Washington, Seattle, USA
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Abhijit Chakraborty
7La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
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Darrin V. Bann
8Division of Otolaryngology - Head & Neck Surgery, Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
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Yanli Wang
5Bioinformatics and Genomics Program, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
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Royden Clark
9Penn State College of Medicine, Informatics and Technology, Hershey, Pennsylvania 17033, USA.
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Lijun Zhang
2Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA.
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Hongbo Yang
2Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA.
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Tingting Liu
2Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA.
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Sriranga Iyyanki
2Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA.
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Lin An
5Bioinformatics and Genomics Program, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
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Christopher Pool
8Division of Otolaryngology - Head & Neck Surgery, Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
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Takayo Sasaki
3Department of Biological Science, 319 Stadium Drive, Florida State University, Tallahassee, Florida 32306-4295, USA.
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Juan Carlos Rivera Mulia
3Department of Biological Science, 319 Stadium Drive, Florida State University, Tallahassee, Florida 32306-4295, USA.
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Hakan Ozadam
4Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
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Bryan R. Lajoie
4Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
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Rajinder Kaul
10Altius institute for Biomedical Sciences 2211 Elliott Avenue, Suite 410, Seattle, WA 98121, USA.
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Michael Buckley
10Altius institute for Biomedical Sciences 2211 Elliott Avenue, Suite 410, Seattle, WA 98121, USA.
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Kristen Lee
10Altius institute for Biomedical Sciences 2211 Elliott Avenue, Suite 410, Seattle, WA 98121, USA.
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Morgan Diegel
10Altius institute for Biomedical Sciences 2211 Elliott Avenue, Suite 410, Seattle, WA 98121, USA.
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Dubravka Pezic
11Research Department of Cancer Biology, Cancer Institute, University College London, London, UK.
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Christina Ernst
12Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
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Suzana Hadjur
11Research Department of Cancer Biology, Cancer Institute, University College London, London, UK.
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Duncan T. Odom
12Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
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John A. Stamatoyannopoulos
10Altius institute for Biomedical Sciences 2211 Elliott Avenue, Suite 410, Seattle, WA 98121, USA.
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James R. Broach
2Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA.
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Ross Hardison
13Center for Comparative Genomics and Bioinformatics, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
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Ferhat Ay
7La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
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  • For correspondence: fyue@hmc.psu.edu gilbert@bio.fsu.edu Job.Dekker@umassmed.edu wnoble@uw.edu ferhatay@lji.org jedixon@salk.edu
William Stafford Noble
6Department of Genome Sciences, University of Washington, Seattle, USA
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  • For correspondence: fyue@hmc.psu.edu gilbert@bio.fsu.edu Job.Dekker@umassmed.edu wnoble@uw.edu ferhatay@lji.org jedixon@salk.edu
Job Dekker
4Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
14Howard Hughes Medical Institute, Boston, MA 02115, USA.
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  • For correspondence: fyue@hmc.psu.edu gilbert@bio.fsu.edu Job.Dekker@umassmed.edu wnoble@uw.edu ferhatay@lji.org jedixon@salk.edu
David M. Gilbert
3Department of Biological Science, 319 Stadium Drive, Florida State University, Tallahassee, Florida 32306-4295, USA.
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  • For correspondence: fyue@hmc.psu.edu gilbert@bio.fsu.edu Job.Dekker@umassmed.edu wnoble@uw.edu ferhatay@lji.org jedixon@salk.edu
Feng Yue
2Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA.
5Bioinformatics and Genomics Program, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
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  • For correspondence: fyue@hmc.psu.edu gilbert@bio.fsu.edu Job.Dekker@umassmed.edu wnoble@uw.edu ferhatay@lji.org jedixon@salk.edu
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Abstract

Structural variants can contribute to oncogenesis through a variety of mechanisms, yet, despite their importance, the identification of structural variants in cancer genomes remains challenging. Here, we present an integrative framework for comprehensively identifying structural variation in cancer genomes. For the first time, we apply next-generation optical mapping, high-throughput chromosome conformation capture (Hi-C), and whole genome sequencing to systematically detect SVs in a variety of cancer cells.

Using this approach, we identify and characterize structural variants in up to 29 commonly used normal and cancer cell lines. We find that each method has unique strengths in identifying different classes of structural variants and at different scales, suggesting that integrative approaches are likely the only way to comprehensively identify structural variants in the genome. Studying the impact of the structural variants in cancer cell lines, we identify widespread structural variation events affecting the functions of non-coding sequences in the genome, including the deletion of distal regulatory sequences, alteration of DNA replication timing, and the creation of novel 3D chromatin structural domains.

These results underscore the importance of comprehensive structural variant identification and indicate that non-coding structural variation may be an underappreciated mutational process in cancer genomes.

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Posted March 28, 2017.
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An Integrative Framework for Detecting Structural Variations in Cancer Genomes
Jesse R. Dixon, Jie Xu, Vishnu Dileep, Ye Zhan, Fan Song, Victoria T. Le, Galip Gürkan Yardimci, Abhijit Chakraborty, Darrin V. Bann, Yanli Wang, Royden Clark, Lijun Zhang, Hongbo Yang, Tingting Liu, Sriranga Iyyanki, Lin An, Christopher Pool, Takayo Sasaki, Juan Carlos Rivera Mulia, Hakan Ozadam, Bryan R. Lajoie, Rajinder Kaul, Michael Buckley, Kristen Lee, Morgan Diegel, Dubravka Pezic, Christina Ernst, Suzana Hadjur, Duncan T. Odom, John A. Stamatoyannopoulos, James R. Broach, Ross Hardison, Ferhat Ay, William Stafford Noble, Job Dekker, David M. Gilbert, Feng Yue
bioRxiv 119651; doi: https://doi.org/10.1101/119651
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An Integrative Framework for Detecting Structural Variations in Cancer Genomes
Jesse R. Dixon, Jie Xu, Vishnu Dileep, Ye Zhan, Fan Song, Victoria T. Le, Galip Gürkan Yardimci, Abhijit Chakraborty, Darrin V. Bann, Yanli Wang, Royden Clark, Lijun Zhang, Hongbo Yang, Tingting Liu, Sriranga Iyyanki, Lin An, Christopher Pool, Takayo Sasaki, Juan Carlos Rivera Mulia, Hakan Ozadam, Bryan R. Lajoie, Rajinder Kaul, Michael Buckley, Kristen Lee, Morgan Diegel, Dubravka Pezic, Christina Ernst, Suzana Hadjur, Duncan T. Odom, John A. Stamatoyannopoulos, James R. Broach, Ross Hardison, Ferhat Ay, William Stafford Noble, Job Dekker, David M. Gilbert, Feng Yue
bioRxiv 119651; doi: https://doi.org/10.1101/119651

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