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Accurate detection of circulating tumor DNA using nanopore consensus sequencing

Alessio Marcozzi, View ORCID ProfileMyrthe Jager, Martin Elferink, Roy Straver, Joost H. van Ginkel, Boris Peltenburg, View ORCID ProfileLi-Ting Chen, Ivo Renkens, Joyce van Kuik, Chris Terhaard, Remco de Bree, Lot A. Devriese, Stefan M. Willems, View ORCID ProfileWigard P. Kloosterman, View ORCID ProfileJeroen de Ridder
doi: https://doi.org/10.1101/2020.07.14.202010
Alessio Marcozzi
1Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
2Cyclomics, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
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Myrthe Jager
1Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
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Martin Elferink
3Department of Genetics, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
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Roy Straver
1Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
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Joost H. van Ginkel
4Department of pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
5Department of Oral and Maxillofacial Surgery, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
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Boris Peltenburg
6Department of Radiotherapy, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands
7Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands
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Li-Ting Chen
1Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
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Ivo Renkens
1Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
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Joyce van Kuik
4Department of pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
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Chris Terhaard
6Department of Radiotherapy, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands
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Remco de Bree
7Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands
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Lot A. Devriese
8Department of Medical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands
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Stefan M. Willems
4Department of pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
9Department of Pathology and Medical Biology, University Medical Center Groningen, Rijksuniversiteit Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
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Wigard P. Kloosterman
2Cyclomics, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
10Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
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  • For correspondence: Wigard@cyclomics.com J.deridder-4@umcutrecht.nl
Jeroen de Ridder
1Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
2Cyclomics, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
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  • For correspondence: Wigard@cyclomics.com J.deridder-4@umcutrecht.nl
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ABSTRACT

Levels of circulating tumor DNA (ctDNA) in liquid biopsies may serve as a sensitive biomarker for real-time, minimally-invasive tumor diagnostics and monitoring. However, detecting ctDNA is challenging, as much fewer than 5% of the cell-free DNA in the blood typically originates from the tumor. To detect lowly abundant ctDNA molecules based on somatic variants, extremely sensitive sequencing methods are required. Here, we describe a new technique, CyclomicsSeq, which is based on Oxford Nanopore sequencing of concatenated copies of a single DNA molecule. Consensus calling of the DNA copies increased the base-calling accuracy ∼60x, enabling accurate detection of TP53 mutations at frequencies down to 0.02%. We demonstrate that a TP53-specific CyclomicsSeq assay can be successfully used to monitor tumor burden during treatment for head-and-neck cancer patients. CyclomicsSeq can be applied to any genomic locus and offers an accurate diagnostic liquid biopsy approach that can be implemented in point-of-care clinical workflows.

Competing Interest Statement

The authors declare the following financial competing interest: A.M., R.S., W.P.K., and J.d.R filed patents and A.M., W.P.K., and J.d.R founded a company (Cyclomics) based on CyclomicsSeq.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Accurate detection of circulating tumor DNA using nanopore consensus sequencing
Alessio Marcozzi, Myrthe Jager, Martin Elferink, Roy Straver, Joost H. van Ginkel, Boris Peltenburg, Li-Ting Chen, Ivo Renkens, Joyce van Kuik, Chris Terhaard, Remco de Bree, Lot A. Devriese, Stefan M. Willems, Wigard P. Kloosterman, Jeroen de Ridder
bioRxiv 2020.07.14.202010; doi: https://doi.org/10.1101/2020.07.14.202010
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Accurate detection of circulating tumor DNA using nanopore consensus sequencing
Alessio Marcozzi, Myrthe Jager, Martin Elferink, Roy Straver, Joost H. van Ginkel, Boris Peltenburg, Li-Ting Chen, Ivo Renkens, Joyce van Kuik, Chris Terhaard, Remco de Bree, Lot A. Devriese, Stefan M. Willems, Wigard P. Kloosterman, Jeroen de Ridder
bioRxiv 2020.07.14.202010; doi: https://doi.org/10.1101/2020.07.14.202010

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