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Nat Genet. 2018 Sep 10. doi: 10.1038/s41588-018-0195-8. [Epub ahead of print]

Integrative detection and analysis of structural variation in cancer genomes.

Author information

1
Salk Institute for Biological Studies, La Jolla, CA, USA. jedixon@salk.edu.
2
Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA, USA.
3
Department of Biological Science, Florida State University, Tallahassee, FL, USA.
4
Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
5
Bioinformatics and Genomics Program, The Pennsylvania State University, University Park, State College, PA, USA.
6
Salk Institute for Biological Studies, La Jolla, CA, USA.
7
Department of Genome Sciences, University of Washington, Seattle, WA, USA.
8
La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.
9
Division of Otolaryngology, Head & Neck Surgery, Milton S. Hershey Medical Center, Hershey, PA, USA.
10
Penn State College of Medicine, Informatics and Technology, Hershey, PA, USA.
11
Altius institute for Biomedical Sciences, Seattle, WA, USA.
12
Research Department of Cancer Biology, Cancer Institute, University College London, London, UK.
13
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
14
German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics, Heidelberg, Germany.
15
Center for Comparative Genomics and Bioinformatics, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, State College, PA, USA.
16
La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA. ferhatay@lji.org.
17
School of Medicine, University of California San Diego, La Jolla, CA, USA. ferhatay@lji.org.
18
Department of Genome Sciences, University of Washington, Seattle, WA, USA. william-noble@uw.edu.
19
Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA. job.dekker@umassmed.edu.
20
Howard Hughes Medical Institute, Chevy Chase, MD, USA. job.dekker@umassmed.edu.
21
Department of Biological Science, Florida State University, Tallahassee, FL, USA. gilbert@bio.fsu.edu.
22
Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA, USA. fyue@hmc.psu.edu.
23
Bioinformatics and Genomics Program, The Pennsylvania State University, University Park, State College, PA, USA. fyue@hmc.psu.edu.

Abstract

Structural variants (SVs) can contribute to oncogenesis through a variety of mechanisms. Despite their importance, the identification of SVs in cancer genomes remains challenging. Here, we present a framework that integrates optical mapping, high-throughput chromosome conformation capture (Hi-C), and whole-genome sequencing to systematically detect SVs in a variety of normal or cancer samples and cell lines. We identify the unique strengths of each method and demonstrate that only integrative approaches can comprehensively identify SVs in the genome. By combining Hi-C and optical mapping, we resolve complex SVs and phase multiple SV events to a single haplotype. Furthermore, we observe widespread structural variation events affecting the functions of noncoding sequences, including the deletion of distal regulatory sequences, alteration of DNA replication timing, and the creation of novel three-dimensional chromatin structural domains. Our results indicate that noncoding SVs may be underappreciated mutational drivers in cancer genomes.

PMID:
30202056
DOI:
10.1038/s41588-018-0195-8

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