Liquid biopsy detection of genomic alterations in pediatric brain tumors from cell-free DNA in peripheral blood, CSF, and urine.

Neuro Oncol

BACKGROUND: The ability to identify genetic alterations in cancers is essential for precision medicine however, surgical approaches to obtain brain tumor tissue are invasive. Profiling circulating-tumor DNA (ctDNA) in liquid biopsies has emerged as a promising approach to avoid invasive procedures. Here, we systematically evaluated the feasibility of profiling pediatric brain tumors using ctDNA obtained from plasma, cerebrospinal fluid (CSF) and urine.

METHODS: We prospectively collected 564 specimens (257 blood, 240 urine, 67 CSF samples) from 258 patients across all histopathologies. We performed ultra-low pass whole-genome sequencing (ULP-WGS) to assess copy number variations and estimate tumor fraction, and developed a pediatric CNS tumor hybrid-capture panel for deep sequencing of specific mutations and fusions.

RESULTS: ULP-WGS detected copy-number alterations in 9/46 (20%) CSF, 3/230 (1.3%) plasma, 0/153 urine samples. Sequencing detected alterations in 3/10 (30%) CSF, 2/74 (2.7%) plasma, 0/2 urine samples. The only positive results were in high-grade tumors. However, most samples had insufficient somatic mutations (median 1, range 0-39) discoverable by the sequencing panel to provide sufficient power to detect tumor fractions of greater than 0.1%.

CONCLUSIONS: Children with brain tumors harbor very low levels of ctDNA in blood, CSF and urine, with CSF having the most DNA detectable. Molecular profiling is feasible in a small subset of high-grade tumors. The level of clonal aberrations per genome is low in most of tumors, posing a challenge for detection using whole genome or even targeted sequencing methods. Substantial challenges therefore remain to genetically characterize pediatric brain tumors from liquid biopsies.

Year of Publication
Neuro Oncol
Date Published
2022 Jan 04
PubMed ID