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Nat Commun. 2019 Jan 23;10(1):392. doi: 10.1038/s41467-018-08200-y.

Exploring the landscape of focal amplifications in cancer using AmpliconArchitect.

Author information

1
Department of Computer Science and Engineering, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. virajbdeshpande@gmail.com.
2
Bioinformatics and Systems Biology Program, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
3
Department of Computer Science and Engineering, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
4
Ludwig Institute for Cancer Research, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
5
Department of Medicine, Division of Hematology-Oncology, School of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
6
Department of Medicine, Division of Medical Genetics, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
7
Moores Cancer Center, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
8
Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
9
Department of Computer Science and Engineering, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. vbafna@cs.ucsd.edu.

Abstract

Focal oncogene amplification and rearrangements drive tumor growth and evolution in multiple cancer types. We present AmpliconArchitect (AA), a tool to reconstruct the fine structure of focally amplified regions using whole genome sequencing (WGS) and validate it extensively on multiple simulated and real datasets, across a wide range of coverage and copy numbers. Analysis of AA-reconstructed amplicons in a pan-cancer dataset reveals many novel properties of copy number amplifications in cancer. These findings support a model in which focal amplifications arise due to the formation and replication of extrachromosomal DNA. Applying AA to 68 viral-mediated cancer samples, we identify a large fraction of amplicons with specific structural signatures suggestive of hybrid, human-viral extrachromosomal DNA. AA reconstruction, integrated with metaphase fluorescence in situ hybridization (FISH) and PacBio sequencing on the cell-line UPCI:SCC090 confirm the extrachromosomal origin and fine structure of a Forkhead box E1 (FOXE1)-containing hybrid amplicon.

PMID:
30674876
PMCID:
PMC6344493
DOI:
10.1038/s41467-018-08200-y
[Indexed for MEDLINE]
Free PMC Article

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