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
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Source: Crossref
Published: Dec 9, 2021
DOI: 10.1038/s41525-021-00272-y
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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 ~60×, 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 clinical workflows.
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