Integrative detection and analysis of structural variation in cancer genomes
Open accessPublished version of a preprint
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.
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Structural variations have the potential to rewire genes with ectopic regulatory elements.
“structural variations have the potential to rewire genes with ectopic regulatory elements”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [23]
A neo-TAD caused by structural variation was associated with higher expression of the oncogene MYC in neuroblastomas.
“For instance, a neo-TAD caused by structural variation was associated with higher expression of the oncogene MYC in neuroblastomas23.”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [23]
Genome structural variations have been shown to cause pathological TAD fusions and create neo-TADs in several cancers.
“Interestingly, genome structural variations have been shown to cause pathological TAD fusions and create neo-TADs in several cancers.”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [23]
The observation of specific changes in Hi-C maps due to different SV types is consistent with findings from a recent study.
“This observation of specific changes in Hi-C maps due to different SV types is consistent with findings from a recent study40.”
From Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer (2020) · cites this paper as [40]
It has been suggested that SVs could lead to TAD fusions (also referred to as neo-TADs).
“Furthermore, it has also been suggested that SVs could lead to TAD fusions40 (also referred to as neo-TADs3,4);”
From Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer (2020) · cites this paper as [40]
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References 89 · Cited by 452
- Authors
- Dixon, J. R., Xu, J., Dileep, V., Zhan, Y., Song, F., Le, V. T., Yardımcı, G. G., Chakraborty, A., Bann, D. V., Wang, Y., Clark, R., Zhang, L., Yang, H., Liu, T., Iyyanki, S., An, L., Pool, C., Sasaki, T., Rivera-Mulia, J. C., Ozadam, H., Lajoie, B. R., Kaul, R., Buckley, M., Lee, K., Diegel, M., Pezic, D., Ernst, C., Hadjur, S., Odom, D. T., Stamatoyannopoulos, J. A., Broach, J. R., Hardison, R. C., Ay, F., Noble, W. S., Dekker, J., Gilbert, D. M., & Yue, F.
- Affiliations
- Salk Institute for Biological Studies (US)
- Pennsylvania State University (US)
- Florida State University (US)
- University of Massachusetts Chan Medical School (US)
- University of Washington (US)
- La Jolla Institute for Immunology (US)
- Penn State Milton S. Hershey Medical Center (US)
- Altius Institute for Biomedical Sciences (US)
- University of Cambridge (GB)
- University College London (GB)
- German Cancer Research Center (DE)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Dixon, Jesse R.
- Ay, Ferhat
- Noble, William Stafford
- Dekker, Job
- Gilbert, David M.
- Yue, Feng
- ORCID
- Dixon, Jesse R.
- Xu, Jie
- Dileep, Vishnu
- Zhan, Ye
- Yardımcı, Galip Gürkan
- Chakraborty, Abhijit
- Bann, Darrin V.
- Wang, Yanli
- Zhang, Lijun
- Yang, Hongbo
- Liu, Tingting
- An, Lin
- Pool, Christopher
- Sasaki, Takayo
- Lajoie, Bryan R.
- Kaul, Rajinder
- Buckley, Michael
- Lee, Kristen
- Ernst, Christina
- Hadjur, Suzana
- Odom, Duncan T.
- Stamatoyannopoulos, John A.
- Broach, James R.
- Hardison, Ross C.
- Ay, Ferhat
- Noble, William Stafford
- Dekker, Job
- Gilbert, David M.
- Yue, Feng
- Venue
- Nature Genetics
- Published
- 2018-09-10
- Volume
- 50
- Issue
- 10
- Pages
- 1388-1398
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6301019
- OpenAlex
- W2891870314
- Cited by
- 452
- References
- 89
- Citations by year
- 2026: 29 · 2025: 28 · 2024: 57 · 2023: 113 · 2022: 47 · 2021: 64 · 2020: 53 · 2019: 45 · 2018: 10 · 2017: 5 · 2014: 1
- FWCI
- 31.74
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- University of Pennsylvania
- Leona M. and Harry B. Helmsley Charitable Trust
- Pennsylvania State University
- Wellcome Trust (202878/Z/16/Z, 84459, 106985/Z/15/Z)
- Penn State Clinical and Translational Science Institute
- Cancer Research UK (20412, 22398)
- National Institutes of Health (DP5OD023071, DK 107980, DK107965, GM085354)
- National Human Genome Research Institute (U41HG007000, R01HG009906, U54HG004592, R01HG003143)
- National Cancer Institute (U01CA200060)
- National Institute of General Medical Sciences (P01GM085354, R01GM083337, R35GM124820)
- National Institute of Diabetes and Digestive and Kidney Diseases (U54DK107965, U54DK107980, R24DK106766)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Keywords
- structural variants, cancer genome, optical mapping, Hi-C, whole genome sequencing, haplotype phasing, DNA replication timing, three-dimensional chromatin structure, carcinogenesis
- MeSH terms
- A549 Cells, Chromosome Mapping, DNA, Neoplasm, Humans, Neoplasms, Genetic Variation, Linkage Disequilibrium, Genome, Human, Sequence Analysis, DNA, Systems Integration, K562 Cells, Cell Line, Tumor, Systems Biology, Genes, Neoplasm, Genomic Structural Variation, High-Throughput Nucleotide Sequencing
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