Dataset Information

Utility of multimodality molecular profiling for pediatric patients with central nervous system tumors.

ABSTRACT:

Background

As our molecular understanding of pediatric central nervous system (CNS) tumors evolves, so too do diagnostic criteria, prognostic biomarkers, and clinical management decision making algorithms. Here, we explore the clinical utility of wide-breadth assays, including whole-exome sequencing (WES), RNA sequencing (RNA-seq), and methylation array profiling as an addition to more conventional diagnostic tools for pediatric CNS tumors.

Methods

This study comprises an observational, prospective cohort followed at a single academic medical center over 3 years. Paired tumor and normal control specimens from 53 enrolled pediatric patients with CNS tumors underwent WES. A subset of cases also underwent RNA-seq (n = 28) and/or methylation array analysis (n = 27).

Results

RNA-seq identified the driver and/or targetable fusions in 7/28 cases, including potentially targetable NTRK fusions, and uncovered possible rationalized treatment options based on outlier gene expression in 23/28 cases. Methylation profiling added diagnostic confidence (8/27 cases) or diagnostic subclassification endorsed by the WHO (10/27 cases). WES detected clinically pertinent tier 1 or tier 2 variants in 36/53 patients. Of these, 16/17 SNVs/INDELs and 10/19 copy number alterations would have been detected by current in-house conventional tests including targeted sequencing panels.

Conclusions

Over a heterogeneous set of pediatric tumors, RNA-seq and methylation profiling frequently yielded clinically relevant information orthogonal to conventional methods while WES demonstrated clinically relevant added value primarily via copy number assessment. Longitudinal cohorts comparing targeted molecular pathology workup vs broader genomic approaches including therapeutic selection based on RNA expression data will be necessary to further evaluate the clinical benefits of these modalities in practice.

SUBMITTER: Rajappa P

PROVIDER: S-EPMC9034114 | biostudies-literature | 2022 Jan-Dec

REPOSITORIES: biostudies-literature

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Publications

Utility of multimodality molecular profiling for pediatric patients with central nervous system tumors.

Rajappa Prajwal P Eng Kenneth W KW Bareja Rohan R Bander Evan D ED Yuan Melissa M Dua Alisha A Bhanu Maachani Uday U Snuderl Matija M Pan Heng H Zhang Tuo T Tosi Umberto U Ivasyk Iryna I Souweidane Mark M MM Elemento Olivier O Sboner Andreas A Greenfield Jeffrey P JP Pisapia David J DJ

Neuro-oncology advances 20220101 1

<h4>Background</h4>As our molecular understanding of pediatric central nervous system (CNS) tumors evolves, so too do diagnostic criteria, prognostic biomarkers, and clinical management decision making algorithms. Here, we explore the clinical utility of wide-breadth assays, including whole-exome sequencing (WES), RNA sequencing (RNA-seq), and methylation array profiling as an addition to more conventional diagnostic tools for pediatric CNS tumors.<h4>Methods</h4>This study comprises an observat ...[more]

PMID: 35475276

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Project description:Pediatric central nervous system tumors remain challenging to diagnose. Imaging approaches do not provide sufficient detail to discriminate between different tumor types, while the histopathological examination of tumor tissue shows high inter-observer variability. Recent studies have demonstrated the accurate classification of central nervous system tumors based on the DNA methylation profile of a tumor biopsy. However, a brain biopsy holds significant risk of bleeding and damaging the surrounding tissues. Liquid biopsy approaches analyzing circulating tumor DNA show high potential as an alternative and less invasive tool to study the DNA methylation pattern of tumors. Here, we explore the potential of classifying pediatric brain tumors based on methylation profiling of the circulating cell-free DNA (cfDNA) in cerebrospinal fluid (CSF). For this proof-of-concept study, we collected cerebrospinal fluid samples from 19 pediatric brain cancer patients via a ventricular drain placed for reasons of increased intracranial pressure. Analyses on the cfDNA showed high variability of cfDNA quantities across patients ranging from levels below the limit of quantification to 40 ng cfDNA per milliliter of CSF. Classification based on methylation profiling of cfDNA from CSF was correct for 7 out of 20 samples in our cohort. Accurate results were mostly observed in samples of high quality, more specifically those with limited high molecular weight DNA contamination. Interestingly, we show that centrifugation of the CSF prior to processing increases the fraction of fragmented cfDNA to high molecular weight DNA. In addition, classification was mostly correct for samples with high tumoral cfDNA fraction as estimated by computational deconvolution (> 40%). In summary, analysis of cfDNA in the CSF shows potential as a tool for diagnosing pediatric nervous system tumors especially in patients with high levels of tumoral cfDNA in the CSF. Further optimization of the collection procedure, experimental workflow and bioinformatic approach is required to also allow classification for patients with low tumoral fractions in the CSF.

Dataset Information

Utility of multimodality molecular profiling for pediatric patients with central nervous system tumors.

Background

Methods

Results

Conclusions

Publications

Utility of multimodality molecular profiling for pediatric patients with central nervous system tumors.

Similar Datasets

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