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Osteosarcoma: Novel prognostic biomarkers using circulating and cell-free tumour DNA

Lyskjær, Iben; Kara, Neesha; De Noon, Solange; Davies, Christopher; Rocha, Ana Maia; Strobl, Anna-Christina; Usher, Inga; ... Flanagan, Adrienne M; + view all (2022) Osteosarcoma: Novel prognostic biomarkers using circulating and cell-free tumour DNA. European Journal of Cancer , 168 pp. 1-11. 10.1016/j.ejca.2022.03.002. Green open access

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Abstract

AIM: Osteosarcoma (OS) is the most common primary bone tumour in children and adolescents. Circulating free (cfDNA) and circulating tumour DNA (ctDNA) are promising biomarkers for disease surveillance and prognostication in several cancer types; however, few such studies are reported for OS. The purpose of this study was to discover and validate methylation-based biomarkers to detect plasma ctDNA in patients with OS and explore their utility as prognostic markers. METHODS: Candidate CpG markers were selected through analysis of methylation array data for OS, non-OS tumours and germline samples. Candidates were validated in two independent OS datasets (n = 162, n = 107) and the four top-performing markers were selected. Methylation-specific digital droplet PCR (ddPCR) assays were designed and experimentally validated in OS tumour samples (n = 20) and control plasma samples. Finally, ddPCR assays were applied to pre-operative plasma and where available post-operative plasma from 72 patients with OS, and findings correlated with outcome. RESULTS: Custom ddPCR assays detected ctDNA in 69% and 40% of pre-operative plasma samples (n = 72), based on thresholds of one or two positive markers respectively. ctDNA was detected in 5/17 (29%) post-operative plasma samples from patients, which in four cases were associated with or preceded disease relapse. Both pre-operative cfDNA levels and ctDNA detection independently correlated with overall survival (p = 0.0015 and p = 0.0096, respectively). CONCLUSION: Our findings illustrate the potential of mutation-independent methylation-based ctDNA assays for OS. This study lays the foundation for multi-institutional collaborative studies to explore the utility of plasma-derived biomarkers in the management of OS.

Type: Article
Title: Osteosarcoma: Novel prognostic biomarkers using circulating and cell-free tumour DNA
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ejca.2022.03.002
Publisher version: https://doi.org/10.1016/j.ejca.2022.03.002
Language: English
Additional information: Crown Copyright © 2022 Published by Elsevier Ltd. Available under the Creative Commons Attribution (CC BY 4.0) licence.
Keywords: Circulating tumour DNA, DNA methylation, Epigenetic biomarkers, Epigenetics, Liquid biopsy, Osteosarcoma, Prognosis
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology
URI: https://discovery.ucl.ac.uk/id/eprint/10146919
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