Optimizing Nanopore sequencing-based detection of structural variants enables individualized circulating tumor DNA-based disease monitoring in cancer patients

• Published in: Genome medicine Vol. 13; no. 1; p. 86
• Main Authors: Valle-Inclan, Jose Espejo, Stangl, Christina, de Jong, Anouk C, van Dessel, Lisanne F, van Roosmalen, Markus J, Helmijr, Jean C A, Renkens, Ivo, Janssen, Roel, de Blank, Sam, de Witte, Chris J, Martens, John W M, Jansen, Maurice P H M, Lolkema, Martijn P, Kloosterman, Wigard P
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 18.05.2021; BioMed Central; BMC
• Subjects: Biomarkers; Biomarkers, Tumor; Biopsy; Cancer; Cancer patients; Care and treatment; Circulating Tumor DNA; Computational Biology - methods; DNA; DNA sequencing; Female; Genetic aspects; Genomes; Genomic Structural Variation; Genomics; Humans; Liquid biopsies; Liquid Biopsy - methods; Male; Metastases; Metastasis; Method; Methods; Molecular Diagnostic Techniques - methods; Molecular Diagnostic Techniques - standards; Nanopore; Nanopore Sequencing; Neoplasms - diagnosis; Neoplasms - genetics; Nucleotide sequencing; Organ Specificity - genetics; Ovarian cancer; Patient monitoring equipment; Patients; Phenols; Polymerase chain reaction; Prostate cancer; Real-Time Polymerase Chain Reaction; Reproducibility of Results; Sensitivity and Specificity; Sequence Analysis, DNA; Structural variation; Netherlands; Liquid biopsies; Nanopore; Genomics; Structural variation; Cancer
• ISSN: 1756-994X; 1756-994X
• DOI: 10.1186/s13073-021-00899-7

Here, we describe a novel approach for rapid discovery of a set of tumor-specific genomic structural variants (SVs), based on a combination of low coverage cancer genome sequencing using Oxford Nanopore with an SV calling and filtering pipeline. We applied the method to tumor samples of high-grade ovarian and prostate cancer patients and validated on average ten somatic SVs per patient with breakpoint-spanning PCR mini-amplicons. These SVs could be quantified in ctDNA samples of patients with metastatic prostate cancer using a digital PCR assay. The results suggest that SV dynamics correlate with and may improve existing treatment-response biomarkers such as PSA. https://github.com/UMCUGenetics/SHARC .