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Minimally invasive classification of pediatric solid tumors using reduced representation bisulfite sequencing of cell-free DNA: a proof-of-principle study

View ORCID ProfileRuben Van Paemel, View ORCID ProfileAndries De Koker, Charlotte Vandeputte, View ORCID ProfileLieke van Zogchel, View ORCID ProfileTim Lammens, View ORCID ProfileGeneviève Laureys, View ORCID ProfileJo Vandesompele, View ORCID ProfileGudrun Schleiermacher, Mathieu Chicard, View ORCID ProfileNadine Van Roy, View ORCID ProfileAles Vicha, View ORCID ProfileG.A.M. Tytgat, View ORCID ProfileNico Callewaert, View ORCID ProfileKatleen De Preter, View ORCID ProfileBram De Wilde
doi: https://doi.org/10.1101/795047
Ruben Van Paemel
1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
2Department of Pediatric Hematology, Oncology & Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
3Cancer Research Institute Ghent (CRIG), Ghent, Belgium
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Andries De Koker
3Cancer Research Institute Ghent (CRIG), Ghent, Belgium
4Center for Medical Biotechnology, Flemish Institute Biotechnology (VIB), Technologiepark 71, B-9052 Ghent, Belgium
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Charlotte Vandeputte
1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
3Cancer Research Institute Ghent (CRIG), Ghent, Belgium
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Lieke van Zogchel
5Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
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Tim Lammens
1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
2Department of Pediatric Hematology, Oncology & Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
3Cancer Research Institute Ghent (CRIG), Ghent, Belgium
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Geneviève Laureys
1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
2Department of Pediatric Hematology, Oncology & Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
3Cancer Research Institute Ghent (CRIG), Ghent, Belgium
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Jo Vandesompele
1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
3Cancer Research Institute Ghent (CRIG), Ghent, Belgium
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Gudrun Schleiermacher
7INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Research Center, Institut Curie, Paris, France
8SiRIC RTOP « Recherche Translationelle en Oncologie Pédiatrique », Institut Curie, Paris, France
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Mathieu Chicard
7INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Research Center, Institut Curie, Paris, France
8SiRIC RTOP « Recherche Translationelle en Oncologie Pédiatrique », Institut Curie, Paris, France
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Nadine Van Roy
1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
3Cancer Research Institute Ghent (CRIG), Ghent, Belgium
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Ales Vicha
6Department of Pediatric Hematology and Oncology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
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G.A.M. Tytgat
5Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
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Nico Callewaert
3Cancer Research Institute Ghent (CRIG), Ghent, Belgium
4Center for Medical Biotechnology, Flemish Institute Biotechnology (VIB), Technologiepark 71, B-9052 Ghent, Belgium
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Katleen De Preter
1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
3Cancer Research Institute Ghent (CRIG), Ghent, Belgium
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Bram De Wilde
1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
2Department of Pediatric Hematology, Oncology & Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
3Cancer Research Institute Ghent (CRIG), Ghent, Belgium
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  • For correspondence: bram.dewilde@ugent.be
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Abstract

In the clinical management of pediatric solid tumors, histological examination of tumor tissue obtained by a biopsy remains the gold standard to establish a conclusive pathological diagnosis. The DNA methylation pattern of a tumor is known to correlate with the histopathological diagnosis across cancer types and is showing promise in the diagnostic workup of tumor samples. This methylation pattern can be detected in the cell-free DNA. Here, we provide proof-of-concept of histopathologic classification of pediatric tumors using cell-free reduced representation bisulfite sequencing (cf-RRBS) from retrospectively collected plasma and cerebrospinal fluid samples. We determined the correct tumor type in 49 out of 60 (81.6%) samples starting from minute amounts (less than 10 ng) of cell-free DNA. We demonstrate that the majority of misclassifications were associated with sample quality and not with the extent of disease. Our approach has the potential to help tackle some of the remaining diagnostic challenges in pediatric oncology in a cost-effective and minimally invasive manner.

Translational relevance Obtaining a correct diagnosis in pediatric oncology can be challenging in some tumor types, especially in renal tumors or central nervous system tumors. Furthermore, the diagnostic odyssey can result in anxiety and discomfort for these children. By applying a novel technique, reduced representation bisulfite sequencing on cell-free DNA (cf-RRBS), we show the feasibility of obtaining the histopathological diagnosis with a minimally invasive test on either plasma or cerebrospinal fluid. Furthermore, we were able to derive the copy number profile or tumor subtype from the same assay. Given that primary tumor material might be difficult to obtain, in particular in critically ill children or depending on the tumor location, and might be limited in terms of quantity or quality, our assay could become complementary to the classical tissue biopsy in difficult cases.

Footnotes

  • added accession identifiers

  • https://github.com/rmvpaeme/cfRRBS_manuscript

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-NC-ND 4.0 International license.
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Posted March 02, 2020.
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Minimally invasive classification of pediatric solid tumors using reduced representation bisulfite sequencing of cell-free DNA: a proof-of-principle study
Ruben Van Paemel, Andries De Koker, Charlotte Vandeputte, Lieke van Zogchel, Tim Lammens, Geneviève Laureys, Jo Vandesompele, Gudrun Schleiermacher, Mathieu Chicard, Nadine Van Roy, Ales Vicha, G.A.M. Tytgat, Nico Callewaert, Katleen De Preter, Bram De Wilde
bioRxiv 795047; doi: https://doi.org/10.1101/795047
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Minimally invasive classification of pediatric solid tumors using reduced representation bisulfite sequencing of cell-free DNA: a proof-of-principle study
Ruben Van Paemel, Andries De Koker, Charlotte Vandeputte, Lieke van Zogchel, Tim Lammens, Geneviève Laureys, Jo Vandesompele, Gudrun Schleiermacher, Mathieu Chicard, Nadine Van Roy, Ales Vicha, G.A.M. Tytgat, Nico Callewaert, Katleen De Preter, Bram De Wilde
bioRxiv 795047; doi: https://doi.org/10.1101/795047

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