Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid

Abstract

Diffuse gliomas comprise the most common malignant brain tumors in adults and include glioblastomas (GBM) and World Health Organization (WHO) grade II and grade III tumors, sometimes referred to as lower-grade gliomas (LGGs). Genetic tumor profiling is used for disease classification and to guide therapy 1 , 2 , but involves brain surgery for tissue collection and repeated tumor biopsies may be necessary for accurate genotyping over the course of the disease 3 – 10 . While detection of circulating tumor DNA (ctDNA) in blood remains challenging for patients with primary brain tumors 11 , 12 , sequencing of cerebrospinal fluid (CSF) ctDNA may provide an alternative to genotype glioma at lower morbidity and cost 13 , 14 . We therefore evaluated the representation of the glioma genome in CSF from 85 glioma patients who underwent a lumbar puncture for evaluation of neurological signs or symptoms. Tumor-derived DNA was detected in CSF from 42/85 (49.4 %) patients and was associated with disease burden and adverse outcome. The genomic landscape of glioma in CSF contained a broad spectrum of genetic alterations and closely resembled the genome in tumor 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 IDH2 1 , 2 , were shared in all matched ctDNA-positive CSF/tumor pairs, whereas we observed considerable evolution in growth factor receptor signaling pathways. The ability to monitor 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.

Leptomeningeal disease in melanoma patients: An update to treatment, challenges, and future directions

“…Limited by several technical constraints, previous somewhat coarse analyses provided limited diagnostic information or pathophysiologic insight. Modern, highly granular analytic approaches to CSF, or “liquid biopsies,” have the potential to greatly improve diagnostic sensitivity of LMD, guide treatment decisions, and drive discovery (Boire et al, , ; Lin et al, ; Miller et al, ). There are two main liquid biopsy approaches currently in use in LMD: circulating tumor cell analysis (CTCs) and cell‐free tumor DNA sequencing (ctDNA); these are reviewed in detail below.…”

New Radiological Classification of Glioma and validation with the survival analysis

“…Advancements like liquid biopsies based on detecting the circulating tumor DNAs in blood are sensitive for neoplasms in other parts of body but poor for glioma (27) probably because of blood brain barrier preventing dissemination of glioma DNA. Some recent studies are using CSF to get the DNAs directly (28) but these techniques are still in research settings.…”

Beyond the Blood: CSF-Derived cfDNA for Diagnosis and Characterization of CNS Tumors

“…In patients with primary brain tumors or CNS metastases, mutant allele frequencies have been shown to decrease with surgical and systemic therapy and correlate with tumor burden (De Mattos-Arruda et al, 2015). Therefore, there is potential that CSF cfDNA could serve as a useful biomarker for monitoring tumor progression and response to therapy (Miller et al, 2019). Moreover, genomic alterations that drive the growth of glioma recurrence are distinct from those present in the initial resection, likely due to tumor evolution (Johnson et al, 2014).…”