Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Cell Free DNA Extracted From Csf for Molecular Diagnosis of Pediatric Embryonal Brain Tumors

Mathieu Chicard
,
Yasmine Iddir
ORCID logo ,
Julien Masliah Planchon
,
Valérie Combaret
,
Valéry Attignon
,
Alexandra Saint-Charles
,
Didier Frappaz
,
Cécile Conter
ORCID logo ,
Kevin Beccaria
,
Pascale Varlet
,
Birgit Geoerger
ORCID logo ,
Sylvain Baulande
ORCID logo ,
Gaelle Pierron
,
Yassine Bouchoucha
,
François Doz
ORCID logo ,
Olivier Delattre
ORCID logo ,
Joshua Waterfall
,
Franck Bourdeaut
,
Gudrun Schleiermacher
* ORCID logo
Version 1 : Received: 6 June 2023 / Approved: 7 June 2023 / Online: 7 June 2023 (05:48:23 CEST)

A peer-reviewed article of this Preprint also exists.

Chicard, M.; Iddir, Y.; Masliah Planchon, J.; Combaret, V.; Attignon, V.; Saint-Charles, A.; Frappaz, D.; Faure-Conter, C.; Beccaria, K.; Varlet, P.; Geoerger, B.; Baulande, S.; Pierron, G.; Bouchoucha, Y.; Doz, F.; Delattre, O.; Waterfall, J.J.; Bourdeaut, F.; Schleiermacher, G. Cell-Free DNA Extracted from CSF for the Molecular Diagnosis of Pediatric Embryonal Brain Tumors. Cancers 2023, 15, 3532. Chicard, M.; Iddir, Y.; Masliah Planchon, J.; Combaret, V.; Attignon, V.; Saint-Charles, A.; Frappaz, D.; Faure-Conter, C.; Beccaria, K.; Varlet, P.; Geoerger, B.; Baulande, S.; Pierron, G.; Bouchoucha, Y.; Doz, F.; Delattre, O.; Waterfall, J.J.; Bourdeaut, F.; Schleiermacher, G. Cell-Free DNA Extracted from CSF for the Molecular Diagnosis of Pediatric Embryonal Brain Tumors. Cancers 2023, 15, 3532.

Abstract

Background: Liquid biopsies are revolutionary tools to detect tumor-specific genetic alterations in body fluids, and cell-free DNA (cfDNA) can be used for molecular diagnosis in cancer patients. In brain tumors cerebrospinal fluid (CSF) cfDNA might be more informative than plasma cfDNA. Here, we assess the use of CSF cfDNA in pediatric embryonal brain tumors (EBT) for molecular diagnosis. Methods: CSF cfDNA of pediatric patients with medulloblastoma (n=18), ATRT (n=3), ETMR (n=1), CNS NB FOXR2 (n=2) and pediatric EBT NOS (n=1) (mean cfDNA concentration 48 ng/mL; range 4-442 ng/mL) and matched tumor genomic DNA were sequenced by WES, and/or a targeted sequencing approach, to determine single nucleotide variations (SNVs)/copy number alterations (CNA). A specific capture covering transcription start sites (TSS) of genes of interest was used for nucleosome footprinting in CSF cfDNA. Results: 15/25 CSF cfDNA samples yielded informative results, with informative CNA and SNVs in 11 and 15 cases, respectively. For cases with paired tumor and CSF cfDNA WES (n=15), a mean of 83 (range 1-160) shared SNVs was observed, including SNVs in classical medulloblastoma genes such as SMO and KMT2D. Interestingly, tumor-specific SNVs (mean 18; range 1-62) or CSF-specific SNVs (mean 5; range 0-25) were observed suggesting clonal heterogeneity. The TSS panel resulted in differential coverage profiles across all 112 studied genes in 7 cases, indicating distinct promoter accessibility. Conclusion: CSF cfDNA sequencing yielded informative results in 60% of cases (15/25), with WES feasible in 83% (15/18). These results pave the way for implementation of these novel approaches for molecular diagnosis and minimal residual disease monitoring.

Keywords

Pediatric embryonal brain tumors, liquid biopsy, cell-free DNA, molecular diagnosis, nucleosome footprinting

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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