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Circulating tumor DNA sequencing provides comprehensive mutation profiling for pediatric central nervous system tumors.

ABSTRACT: Molecular profiling of childhood CNS tumors is critical for diagnosis and clinical management, yet tissue access is restricted due to the sensitive tumor location. We developed a targeted deep sequencing platform to detect tumor driver mutations, copy number variations, and heterogeneity in the liquid biome. Here, we present the sensitivity, specificity, and clinical relevance of our minimally invasive platform for tumor mutation profiling in children diagnosed with CNS cancer.

SUBMITTER: Bonner ER

PROVIDER: S-EPMC9448784 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Circulating tumor DNA sequencing provides comprehensive mutation profiling for pediatric central nervous system tumors.

Bonner Erin R ER Harrington Robin R Eze Augustine A Bornhorst Miriam M Kline Cassie N CN Gordish-Dressman Heather H Dawood Adam A Das Biswajit B Chen Li L Pauly Rini R Williams P Mickey PM Karlovich Chris C Peach Amanda A Howell D'andra D Doroshow James J Kilburn Lindsay L Packer Roger J RJ Mueller Sabine S Nazarian Javad J

NPJ precision oncology 20220906 1

Molecular profiling of childhood CNS tumors is critical for diagnosis and clinical management, yet tissue access is restricted due to the sensitive tumor location. We developed a targeted deep sequencing platform to detect tumor driver mutations, copy number variations, and heterogeneity in the liquid biome. Here, we present the sensitivity, specificity, and clinical relevance of our minimally invasive platform for tumor mutation profiling in children diagnosed with CNS cancer. ...[more]

PMID: 36068285

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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

Circulating tumor DNA sequencing provides comprehensive mutation profiling for pediatric central nervous system tumors.

Publications

Circulating tumor DNA sequencing provides comprehensive mutation profiling for pediatric central nervous system tumors.

Similar Datasets

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