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Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid.

ABSTRACT: Diffuse gliomas are the most common malignant brain tumours in adults and include glioblastomas and World Health Organization (WHO) grade II and grade III tumours (sometimes referred to as lower-grade gliomas). Genetic tumour profiling is used to classify disease and guide therapy1,2, but involves brain surgery for tissue collection; repeated tumour biopsies may be necessary for accurate genotyping over the course of the disease3-10. While the detection of circulating tumour DNA (ctDNA) in the blood of patients with primary brain tumours remains challenging11,12, sequencing of ctDNA from the cerebrospinal fluid (CSF) may provide an alternative way to genotype gliomas with lower morbidity and cost13,14. We therefore evaluated the representation of the glioma genome in CSF from 85 patients with gliomas who underwent a lumbar puncture because they showed neurological signs or symptoms. Here we show that tumour-derived DNA was detected in CSF from 42 out of 85 patients (49.4%) and was associated with disease burden and adverse outcome. The genomic landscape of glioma in the CSF included a broad spectrum of genetic alterations and closely resembled the genomes of tumour biopsies. Alterations that occur early during tumorigenesis, such as co-deletion of chromosome arms 1p and 19q (1p/19q codeletion) and mutations in the metabolic genes isocitrate dehydrogenase 1 (IDH1) or IDH21,2, were shared in all matched ctDNA-positive CSF-tumour pairs, whereas growth factor receptor signalling pathways showed considerable evolution. The ability to monitor the evolution of the glioma genome through a minimally invasive technique could advance the clinical development and use of genotype-directed therapies for glioma, one of the most aggressive human cancers.

SUBMITTER: Miller AM

PROVIDER: S-EPMC6457907 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid.

Miller Alexandra M AM Shah Ronak H RH Pentsova Elena I EI Pourmaleki Maryam M Briggs Samuel S Distefano Natalie N Zheng Youyun Y Skakodub Anna A Mehta Smrutiben A SA Campos Carl C Hsieh Wan-Ying WY Selcuklu S Duygu SD Ling Lilan L Meng Fanli F Jing Xiaohong X Samoila Aliaksandra A Bale Tejus A TA Tsui Dana W Y DWY Grommes Christian C Viale Agnes A Souweidane Mark M MM Tabar Viviane V Brennan Cameron W CW Reiner Anne S AS Rosenblum Marc M Panageas Katherine S KS DeAngelis Lisa M LM Young Robert J RJ Berger Michael F MF Mellinghoff Ingo K IK

Nature 20190123 7741

Diffuse gliomas are the most common malignant brain tumours in adults and include glioblastomas and World Health Organization (WHO) grade II and grade III tumours (sometimes referred to as lower-grade gliomas). Genetic tumour profiling is used to classify disease and guide therapy<sup>1,2</sup>, but involves brain surgery for tissue collection; repeated tumour biopsies may be necessary for accurate genotyping over the course of the disease<sup>3-10</sup>. While the detection of circulating tumou ...[more]

PMID: 30675060

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Project description:BackgroundCerebrospinal fluid (CSF) plays an important role in maintaining tissue homeostasis in the central nervous system. In 2012, the new CSF outflow pathway, "the glymphatic system," was discovered. The glymphatic system mediates CSF and interstitial fluid exchange through the perivascular pathway, which eliminates harmful solutes in the brain parenchyma. In recent studies, the importance of the glymphatic system has been demonstrated in healthy and neurodegenerative disease brains. However, there is limited research on the function of the CSF in brain tumors. Intracranial hypertension caused by glioma can affect CSF drainage, which impacts the delivery of chemotherapy drugs via intrathecal injection. This study focused on changes in the glymphatic system and the role of aquaporin 4 (AQP4) in glymphatic transport in glioma.MethodsIn glioma-bearing rats, the effect of tracer infusion on the intracranial pressure (ICP) was evaluated using an ICP microsensor. In vivo magnetic resonance imaging and ex vivo bright field were used to monitor CSF tracer distribution after cisterna magna injection. AQP4 expression was quantitatively detected, and AQP4 in the astrocytes around the vessels was observed using immunofluorescence.ResultsThe ICP of the tumor group was higher than that of the control group and the infusion rate of 2 µl/min did not affect ICP. In vivo and ex vivo imaging showed that the circulation of CSF tracers was significantly impaired in the tumor. High-power confocal microscopy revealed that, in the tumor, the surrounding of AQP4 by Evans Blue was decreased. In both tumor and contralateral areas, data indicated that the number of cluster designation 34 (CD34+) alpha-smooth muscle actin (α-SMA-) veins were more than that of CD34+α-SMA+ arteries. Moreover, in the tumor area, AQP4 in the astrocytes around the vessels was decreased.ConclusionsThese findings indicate that the para-arterial influx of subarachnoid CSF is limited in glioma, especially in those with reduced levels of the fundamental protein AQP4. Our results provide evidence toward a potential new treatment method for glioma in the future.

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Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid.

Publications

Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid.

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