Abstract 3755: AmpliconSuite enables discovery of extrachromosomal DNA in tumor genomes

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Abstract Focal amplifications in the cancer genome, particularly extrachromosomal DNA (ecDNA) amplifications, are a pivotal event in cancer progression across diverse cancer contexts. These megabase-scale circular structures arise when DNA breaks off chromosomes, accumulating hundreds of copies per cell through asymmetric segregation and positive selection for oncogenic elements. While previously thought to be a late-stage consequence of genome instability, recent evidence suggests ecDNA may arise as early as pre-cancer and associate with malignant transformation (Luebeck et al., Nature 2023). However, identifying and delineating these distinct events from other modes of amplification using whole-genome sequencing (WGS) data remains challenging due to their complex profiles of copy number and structural variation. We present AmpliconSuite, a comprehensive workflow that robustly identifies focal amplifications from WGS data. At its core is the AmpliconArchitect (AA) module, which jointly analyzes structural variants and copy numbers. AA has been deployed on thousands of samples, helping elucidate the role of ecDNA in cancer. AmpliconSuite enhances reproducibility by providing a seamless end-to-end workflow: upstream, it standardizes identification of candidate focal amplification regions, and downstream, it uses AmpliconClassifier to report amplification mechanisms. The workflow has been extensively validated on a cytogenetic-backed dataset of over 150 cancer cell-line/gene probe combinations. Its easily-interpretable tabular outputs annotate gene contents, copy numbers, and summarize structural complexity of amplicons. AmpliconSuite can be run on cloud.genepattern.org, requiring only a web browser, which enables cloud-based "push button" bioinformatic analysis. To date, it has been deployed across more than 30 large-scale studies, processing over 45,000 tumor samples and three petabytes of sequencing data. We introduced novel methods to categorize ecDNA types by matching structural variation patterns to formation mechanisms. Our approach distinguishes ecDNA generated by chromothripsis from those arising from excisional models or stalled replication forks, validated against engineered ecDNA formation systems (Shoshani et al., Nature 2021, Pradella et al., Nature 2024). Complementing the tool is AmpliconRepository.org, a community-editable platform for sharing focal amplification calls. It allows researchers to share results publicly or privately and currently provides ecDNA predictions for over 4,500 tumor samples from TCGA, PCAWG, CCLE, and other datasets. AmpliconSuite advances our understanding of ecDNA biology by providing a reproducible, user-friendly tool that reveals novel insights into extrachromosomal DNA formation, breakage-fusion-bridges, and other mechanisms of oncogene amplification. Citation Format: Jens Luebeck, Edwin Huang, Ted Liefeld, Forrest Kim, Ivy T. Wong, Bhargavi Dameracharla, Gino Prasad, Rohil Ahuja, Daniel Schreyer, Kaiyuan Zhu, Rishaan Kenkre, Tushar Agashe, Devika Torvi, Soyeon Kim, Hoon Kim, Peter Bailey, Roel G. Verhaak, Viraj Deshpande, Michael Reich, Paul S. Mischel, Jill Mesirov, Vineet Bafna. AmpliconSuite enables discovery of extrachromosomal DNA in tumor genomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3755.

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