Classification of Brain Tumors by Nanopore Sequencing of Cell-Free DNA from Cerebrospinal Fluid

脑脊液 胎儿游离DNA 病理 脑瘤 DNA测序 DNA甲基化 室管膜瘤 DNA 液体活检 生物 医学 基因 癌症 遗传学 基因表达 怀孕 产前诊断 胎儿
作者
Ann‐Kristin Afflerbach,Christian Rohrandt,Björn Brändl,Marthe Sönksen,Jürgen Hench,Stephan Frank,Daniela Börnigen,Malik Alawi,Martin Mynarek,Beate Winkler,Franz Ricklefs,Michael Synowitz,Lasse Dührsen,Stefan Rutkowski,Annika K. Wefers,Frank Müller,Melanie Schoof,Ulrich Schüller
出处
期刊:Clinical Chemistry [American Association for Clinical Chemistry]
卷期号:70 (1): 250-260 被引量:40
标识
DOI:10.1093/clinchem/hvad115
摘要

Abstract Background Molecular brain tumor diagnosis is usually dependent on tissue biopsies or resections. This can pose several risks associated with anesthesia or neurosurgery, especially for lesions in the brain stem or other difficult-to-reach anatomical sites. Apart from initial diagnosis, tumor progression, recurrence, or the acquisition of novel genetic alterations can only be proven by re-biopsies. Methods We employed Nanopore sequencing on cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) and analyzed copy number variations (CNV) and global DNA methylation using a random forest classifier. We sequenced 129 samples with sufficient DNA. These samples came from 99 patients and encompassed 22 entities. Results were compared to clinical diagnosis and molecular analysis of tumor tissue, if available. Results 110/129 samples were technically successful, and 50 of these contained detectable circulating tumor DNA (ctDNA) by CNV or methylation profiling. ctDNA was detected in samples from patients with progressive disease but also from patients without known residual disease. CNV plots showed diagnostic and prognostic alterations, such as C19MC amplifications in embryonal tumors with multilayered rosettes or Chr.1q gains and Chr.6q losses in posterior fossa group A ependymoma, respectively. Most CNV profiles mirrored the profiles of the respective tumor tissue. DNA methylation allowed exact classification of the tumor in 22/110 cases and led to incorrect classification in 2/110 cases. Only 5/50 samples with detected ctDNA contained tumor cells detectable through microscopy. Conclusions Our results suggest that Nanopore sequencing data of cfDNA from CSF samples may be a promising approach for initial brain tumor diagnostics and an important tool for disease monitoring.
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