Exploring the landscape of focal amplifications in cancer using AmpliconArchitect

Viraj Deshpande (), Jens Luebeck, Nam-Phuong D. Nguyen, Mehrdad Bakhtiari, Kristen M. Turner, Richard Schwab, Hannah Carter, Paul S. Mischel and Vineet Bafna ()
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Viraj Deshpande: University of California at San Diego
Jens Luebeck: University of California at San Diego
Nam-Phuong D. Nguyen: University of California at San Diego
Mehrdad Bakhtiari: University of California at San Diego
Kristen M. Turner: University of California at San Diego
Richard Schwab: University of California at San Diego
Hannah Carter: University of California at San Diego
Paul S. Mischel: University of California at San Diego
Vineet Bafna: University of California at San Diego

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08200-y

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