Next-generation sequencing of cerebrospinal fluid for clinical molecular diagnostics in pediatric, adolescent and young adult brain tumor patients.

Abstract

BACKGROUND:

Safe sampling of central nervous system tumor tissue for diagnostic purposes may be difficult if not impossible, especially in pediatric patients, and an unmet need exists to develop less invasive diagnostic tests.

METHODS:

We report our clinical experience with minimally invasive molecular diagnostics using a clinically validated assay for sequencing of cerebrospinal fluid (CSF) cell-free DNA (cfDNA). All CSF samples were collected as part of clinical care, and results reported to both clinicians and patients/families.

RESULTS:

We analyzed 64 CSF samples from 45 pediatric, adolescent and young adult (AYA) patients (pediatric = 25; AYA = 20) with primary and recurrent brain tumors across 12 histopathological subtypes including high-grade glioma (n = 10), medulloblastoma (n = 10), pineoblastoma (n = 5), low-grade glioma (n = 4), diffuse leptomeningeal glioneuronal tumor (DLGNT) (n = 4), retinoblastoma (n = 4), ependymoma (n = 3), and other (n = 5). Somatic alterations were detected in 30/64 samples (46.9%) and in at least one sample per unique patient in 21/45 patients (46.6%). CSF cfDNA positivity was strongly associated with the presence of disseminated disease at the time of collection (81.5% of samples from patients with disseminated disease were positive). No association was seen between CSF cfDNA positivity and the timing of CSF collection during the patient's disease course.

CONCLUSIONS:

We identified three general categories where CSF cfDNA testing provided additional relevant diagnostic, prognostic, and/or therapeutic information, impacting clinical assessment and decision making: (1) diagnosis and/or identification of actionable alterations; (2) monitor response to therapy; and (3) tracking tumor evolution. Our findings support broader implementation of clinical CSF cfDNA testing in this population to improve care.

• Authors: Alexandra M Miller, Luca Szalontay, Nancy Bouvier, Katherine Hill, Hamza Ahmad, Johnathan Rafailov, Alex J Lee, M Irene Rodriguez-Sanchez, Onur Yildirim, Arti Patel, Tejus A Bale, Jamal K Benhamida, Ryma Benayed, Maria E Arcila, Maria Donzelli, Ira J Dunkel, Stephen W Gilheeney, Yasmin Khakoo, Kim Kramer, Sameer F Sait, Jeffrey P Greenfield, Mark M Souweidane, Sofia Haque, Audrey Mauguen, Michael F Berger, Ingo K Mellinghoff, Matthias A Karajannis
• Journal: Neuro-oncology (Neuro Oncol) Vol. 24 Issue 10 Pg. 1763-1772 (10 03 2022) ISSN: 1523-5866 [Electronic] England
• PMID: 35148412 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Cell-Free Nucleic Acids

Topics

• Adolescent
• Brain Neoplasms (diagnosis, genetics, pathology)
• Cell-Free Nucleic Acids (cerebrospinal fluid)
• Central Nervous System Neoplasms
• Child
• Glioma (genetics)
• High-Throughput Nucleotide Sequencing
• Humans
• Mutation
• Pathology, Molecular
• Young Adult