Introduction: Our laboratory has previously reported the development of urinary biomarkers capable of identifying the presence of tumors of the central nervous system (CNS). Building on this general screening panel, we now describe a tumor-specific panel of non-invasive biomarkers detectable in urine and capable of predicting the presence of the most common malignant pediatric brain tumor, medulloblastoma.
Methods: Urine, cerebrospinal fluid, and tissue specimens were collected from pediatric patients (<21 years of age) with pathology-proven medulloblastoma (n=16). Zymography, ELISA, and immunohistochemistry were used to characterize a panel of putative biomarkers derived from a family of related extracellular matrix (ECM) peptidases and regulatory proteins. Results were compared between age- and sex-matched controls and subjected to univariate and multivariate statistical analyses. Biomarker levels in the medulloblastoma-specific panel were compared against levels in other categories of CNS disease (non-medulloblastoma tumors, arteriovenous malformations, moyamoya) to assess the utility of the panel in discriminating the presence of medulloblastoma.
Results: Analysis revealed significant elevations of 4 interrelated molecules: two proteases and two inhibitors of associated proteases (all P < 0.05) - and significant reduction of a subfamily of an inhibitory enzyme (P < 0.05) in medulloblastoma patients as compared with controls. Multiplexing pairs of these molecules provided superior accuracy compared with any individual biomarker. Receiver-operating characteristics curves for the markers showed excellent discrimination. Subgroup analysis revealed that use of this panel successfully identified medulloblastoma when compared to other categories of CNS disease.
Conclusions: We report, for the first time, the identification of a specific panel of 5 functionally-related biomarkers which can be detected non-invasively in the urine and successfully predict the presence of a specific subtype of pediatric brain tumor, medulloblastoma. These data support the potential utility of urinary biomarkers in the detection of pediatric brain tumors and the possibility of tumor-specific “fingerprinting” profiles.
Patient Care: This approach offers a number of innovative advantages particularly relevant to pediatric brain tumors. Current methods of diagnosis and follow-up rely on infrequent clinical examinations and expensive radiographic studies (such as MRI) that often require sedation or anesthesia in children. By contrast, urine collection carries no risks and is less expensive (at our institution, urine collection and analysis costs 10- to 100-times less than MRIs) so it can easily be done at shorter intervals than are currently practical for imaging studies, enabling earlier detection of recurrent disease. Collection of urine specimens is easy and non-invasive, avoiding the difficulties and risk inherent to lumbar punctures and venipuncture – especially important with children. Urine collection can be done locally and mailed, saving families travel to tertiary care centers. Significantly, biomarkers provide a method of tumor diagnosis that relies on metabolic activity; a different – and complementary – approach to the current method of visual evaluation made with imaging studies. Most importantly, the ability to provide an “early-warning system” to detect new tumors and identify recurrent disease removes a major obstacle to substantially improving the survival and quality of life for children afflicted with these tumors.
Learning Objectives: By the conclusion of this session, participants should be able to:
1) Describe the importance of recognizing the potential for urinary biomarkers to identify pediatric brain tumors
2) Discuss, in small groups, the utility of non-invasive biomarkers in neurosurgery
3) Identify effective uses for biomarker fingerprinting to aid in the treatment and follow-up of children with tumors of the CNS.