Reconstructing extrachromosomal DNA structural heterogeneity from long-read sequencing data using Decoil
- Mădălina Giurgiu1,2,3,4,
- Nadine Wittstruck1,2,3,
- Elias Rodriguez-Fos1,2,3,
- Rocío Chamorro González1,2,3,5,
- Lotte Brückner1,2,3,5,
- Annabell Krienelke-Szymansky1,2,3,
- Konstantin Helmsauer1,2,3,
- Anne Hartebrodt6,
- Philipp Euskirchen7,8,
- Richard P. Koche9,
- Kerstin Haase1,2,3,10,
- Knut Reinert4,10 and
- Anton G. Henssen1,2,3,5,10
- 1Department of Pediatric Oncology and Hematology, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany;
- 2Experimental and Clinical Research Center of the Max Delbrück Center and Charité Berlin, 13125 Berlin, Germany;
- 3Charité–Universitätsmedizin Berlin, 10117 Berlin, Germany;
- 4Freie Universität Berlin, 14195 Berlin, Germany;
- 5Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany;
- 6Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany;
- 7German Cancer Consortium (DKTK), partner site Berlin, a partnership between DKFZ and Charité–Universitätsmedizin Berlin, 10117 Berlin, Germany;
- 8Department of Neuropathology, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany;
- 9Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
-
↵10 These authors contributed equally to this work.
Abstract
Circular extrachromosomal DNA (ecDNA) is a form of oncogene amplification found across cancer types and associated with poor outcome in patients. ecDNA can be structurally complex and can contain rearranged DNA sequences derived from multiple chromosome locations. As the structure of ecDNA can impact oncogene regulation and may indicate mechanisms of its formation, disentangling it at high resolution from sequencing data is essential. Even though methods have been developed to identify and reconstruct ecDNA in cancer genome sequencing, it remains challenging to resolve complex ecDNA structures, in particular amplicons with shared genomic footprints. We here introduce Decoil, a computational method that combines a breakpoint-graph approach with LASSO regression to reconstruct complex ecDNA and deconvolve co-occurring ecDNA elements with overlapping genomic footprints from long-read nanopore sequencing. Decoil outperforms de novo assembly and alignment-based methods in simulated long-read sequencing data for both simple and complex ecDNAs. Applying Decoil on whole-genome sequencing data uncovered different ecDNA topologies and explored ecDNA structure heterogeneity in neuroblastoma tumors and cell lines, indicating that this method may improve ecDNA structural analyses in cancer.
Footnotes
-
[Supplemental material is available for this article.]
-
Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.279123.124.
-
Freely available online through the Genome Research Open Access option.
- Received February 15, 2024.
- Accepted July 29, 2024.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
