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 disease3,4,5,6,7,8,9,10. 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.
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All genomic results and associated clinical data for all patients in this study are publically available in the cBioPortal for Cancer Genomics at the following URL: http://www.cbioportal.org/study?id=glioma_msk_2018. The MSK-IMPACT data analysis pipeline can be found here: https://github.com/rhshah/IMPACT-Pipeline. The source data for Table 1 and Extended Data Fig. 1 are available in Supplementary Table 1. The source data for the multivariable analysis (Extended Data Table 2) are available in Supplementary Table 2. The source data for the matched pair analysis (Fig. 2a, b) are available in Supplementary Table 5 (separate MS Excel file).
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This research was supported by the National Brain Tumor Society Defeat GBM Initiative (I.K.M.), the National Institutes of Health (1 R35 NS105109 01 and P30CA008748), Cycle of Survival (I.K.M.), the American Brain Tumor Association (E.I.P.), the Marie Josée and Henry R. Kravis Center for Molecular Oncology, the MSK Brain Tumor Center, and the MSK Neuro-Oncology Research in Translation (NORTH) Program.
Nature thanks A. Bardelli, O. Rueda, M. Taylor and R. Verhaak for their contribution to the peer review of this work.