The Use of Cerebrospinal Fluid in Medulloblastoma Biomarkers Studies

Medulloblastoma is the most common malignant tumor of the cerebellum in children, and it accounts for 15% of pediatric central nervous system (CNS) tumors. Medulloblastoma has a propensity to invade and disseminate in the cerebrospinal fluid (CSF), with disseminated CNS disease occurring in 30–40% of cases at initial diagnosis and most patients at recurrence. The current diagnosis of Medulloblastoma is based on clinical assessment, imaging, and subsequent histopathological examination of biopsies, with magnetic resonance imaging and lumbar puncture often performed to monitor treatment responses and to detect recurrences. Although recent advances in imaging have improved Medulloblastoma detection and monitoring, there remain unmet needs for diagnostics to sensitively detect the disease at both initial presentation and at recurrence.

Despite this considerable progress in the molecular characterization of medulloblastoma, the biology and impact of the disease on the CSF microenvironment is still poorly understood, despite the tumor microenvironment contributing to cancer progression, metastasis, and resistance and potentially providing a rich source of biomarkers that can be sampled relatively non-invasively to chart the course of disease.

Liquid biopsies a term refer to the molecular analysis of biofluids is a minimally-invasive method that shows promise for disease detection and monitoring through the measurement of circulating tumor cells, DNA, RNA, or extracellular vesicles in the urine, CSF, and blood samples. Although blood has most commonly been used as the biofluid of choice for liquid biopsy, its sensitivity for CNS tumors tends to be poor due to biomarkers of interest not crossing the blood–brain barrier. However, CSF bathes the brain and spinal cord and therefore provides a window to tumors arising in the CNS and disseminating in the CSF. Furthermore, many patients with MB have hydrocephalus that needs to be drained to reduce intracranial pressure and prior to surgery. Many studies have attempted to detect biomarkers in the CSF in adult patients with CNS tumors, but few have analyzed the metabolite, lipid, transcriptomic, and genomic profiles in the CSF of children. To date, there has yet to be an integrated analysis of the transcriptomic, metabolomic, and lipidomic changes occurring in the CSF of children with medulloblastoma. The experiments are technically challenging because global RNA-sequencing of messenger RNAs (mRNAs) and circular RNAs (circRNAs) in CSF, is in low concentrations and susceptible to fragmentation and degradation; and secondly the ability to profile metabolites and lipids, which have only recently been facilitated by the advent of high-resolution, high-sensitivity, and high mass accuracy mass spectrometers..

To obtain an integrated understanding of the pathobiological impact of medulloblastoma on the surrounding microenvironment of the CSF and as a precursor to biomarker identification, Johns Hopkins University scientists led by Professor Ranjan Perera, director of the Center for RNA Biology at Johns Hopkins All Children’s Hospital, analyzed the transcriptomic, metabolomic, and lipidomic landscapes of CSF samples obtained from forty patients with primary or recurrent medulloblastoma and eleven normal controls. In doing so, they establish that patients with medulloblastoma have a unique transcriptomic, metabolomic, and lipidomic landscape in their CSF that might be helpful for diagnosis and monitoring and that reflects biological changes consistent with the presence of medulloblastoma in the CNS. The original research article is now published in the journal Acta Neuropathologica Communications.

Comparing cerebrospinal fluid samples from 40 patients with medulloblastoma and from 11 healthy children without the disease, the investigators successfully identified 110 genes, 10 types of RNA, 14 lipids and several metabolites that were expressed differently between the two groups. While these details were not specific enough to distinguish among subtypes of medulloblastoma, they could be used in the future to identify the presence of cancer versus normal fluid.