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Bruzek, Amy K.; Ravi, Karthik; Muruganand, Ashwath; Wadden, Jack; Babila, Clarissa May; Cantor, Evan; Tunkle, Leo; Wierzbicki, Kyle; Stallard, Stefanie; Dickson, Robert P.; Wolfe, Ian; Mody, Rajen; Schwartz, Jonathan; Franson, Andrea; Robertson, Patricia L.; Muraszko, Karin M.; Maher, Cormac O.; Garton, Hugh J.L.; Qin, Tingtin; Koschmann, Carl

Electronic DNA Analysis of CSF Cell-free Tumor DNA to Quantify Multi-gene Molecular Response in Pediatric High-grade Glioma

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  • Medientyp: E-Artikel
  • Titel: Electronic DNA Analysis of CSF Cell-free Tumor DNA to Quantify Multi-gene Molecular Response in Pediatric High-grade Glioma
  • Beteiligte: Bruzek, Amy K.; Ravi, Karthik; Muruganand, Ashwath; Wadden, Jack; Babila, Clarissa May; Cantor, Evan; Tunkle, Leo; Wierzbicki, Kyle; Stallard, Stefanie; Dickson, Robert P.; Wolfe, Ian; Mody, Rajen; Schwartz, Jonathan; Franson, Andrea; Robertson, Patricia L.; Muraszko, Karin M.; Maher, Cormac O.; Garton, Hugh J.L.; Qin, Tingtin; Koschmann, Carl
  • Erschienen: American Association for Cancer Research (AACR), 2020
  • Erschienen in: Clinical Cancer Research, 26 (2020) 23, Seite 6266-6276
  • Sprache: Englisch
  • DOI: 10.1158/1078-0432.ccr-20-2066
  • ISSN: 1078-0432; 1557-3265
  • Schlagwörter: Cancer Research ; Oncology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>Pediatric high-grade glioma (pHGG) diagnosis portends poor prognosis and therapeutic monitoring remains difficult. Tumors release cell-free tumor DNA (cf-tDNA) into cerebrospinal fluid (CSF), allowing for potential detection of tumor-associated mutations by CSF sampling. We hypothesized that direct, electronic analysis of cf-tDNA with a handheld platform (Oxford Nanopore MinION) could quantify patient-specific CSF cf-tDNA variant allele fraction (VAF) with improved speed and limit of detection compared with established methods.</jats:p> </jats:sec> <jats:sec> <jats:title>Experimental Design:</jats:title> <jats:p>We performed ultra-short fragment (100–200 bp) PCR amplification of cf-tDNA for clinically actionable alterations in CSF and tumor samples from patients with pHGG (n = 12) alongside nontumor CSF (n = 6). PCR products underwent rapid amplicon-based sequencing by Oxford Nanopore Technology (Nanopore) with quantification of VAF. Additional comparison to next-generation sequencing (NGS) and droplet digital PCR (ddPCR) was performed.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>Nanopore demonstrated 85% sensitivity and 100% specificity in CSF samples (n = 127 replicates) with 0.1 femtomole DNA limit of detection and 12-hour results, all of which compared favorably with NGS. Multiplexed analysis provided concurrent analysis of H3.3A (H3F3A) and H3C2 (HIST1H3B) mutations in a nonbiopsied patient and results were confirmed by ddPCR. Serial CSF cf-tDNA sequencing by Nanopore demonstrated correlation of radiological response on a clinical trial, with one patient showing dramatic multi-gene molecular response that predicted long-term clinical response.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>Nanopore sequencing of ultra-short pHGG CSF cf-tDNA fragments is feasible, efficient, and sensitive with low-input samples thus overcoming many of the barriers restricting wider use of CSF cf-tDNA diagnosis and monitoring in this patient population.</jats:p> </jats:sec>
  • Zugangsstatus: Freier Zugang