Introduction: Netrin-1 is an axon guidance factor implicated in development and tumorigenesis. Here we report the use of netrin-1 as a non-invasive urinary biomarker for medulloblastoma with specific focus on the novel application of correlating biomarker levels with prognostic risk.
Methods: Urine was collected from 28 pediatric patients (1-18 years of age), focusing on those with medulloblastoma (n=16, as confirmed by both imaging and subsequent surgical pathology) and compared to age- and sex-matched controls (n=12), following an IRB approved protocol. Tumor size, location and Chang stage were evaluated, along with Children’s Cancer Group high/low risk status. ELISA was used to quantify the levels of urinary netrin-1 and data was normalized to protein concentration using Bradford assays. Cerebrospinal fluid (CSF) was also evaluated, along with tissue subjected to immunohistochemistry. Results were subjected to univariate and multivariate statistical analyses.
Results: Receiver operating characteristic (ROC) curve analysis indicated that urinary netrin-1 provided excellent diagnostic accuracy as a predictive biomarker in differentiating between tumor and control groups (area under the curve [AUC]: 0.875, p<0.001). The Youden index and multivariable logistic regression indicated that the odds of medulloblastoma were estimated to be over 12 times greater for patients with urinary netrin-1 levels over 2.3 pg/µg (odds ratio: 12.6, 95%; CI: 2.1-47.5, p=0.002) Patients with invasive tumors (High Risk: 8.3 pg/ug) had urinary netrin-1 levels approximately five times greater than patients with non-invasive tumors (Low Risk: 1.6 pg/µg, n=7, p=0.002)
Conclusions: Netrin-1 demonstrates the potential role of urinary biomarkers in diagnosing medulloblastoma. This biomarker correlates not only with presence of disease but also with existing methods of predicting outcome. These data support the hypothesis that the use of urinary biomarkers may have utility as a novel, noninvasive method to identify medulloblastoma in children and reveals a potential biological pathway that directly associates expression of a specific molecule with clinical prognosis.
Patient Care: This research is designed to develop novel, non-invasive diagnostic and prognostic biomarkers directly able to impact the treatment of children with brain tumors and cerebrovascular disease.
Learning Objectives: By the conclusion of this session, participants should be able to:
1) Describe the importance of urinary biomarkers as novel diagnostic tools.
2) Discuss, in small groups, the advantages and shortcomings of non-invasive methods of brain tumor diagnosis and follow-up.
3) Identify an effective panel of molecules - including netrin-1 - able to assist in the diagnosis of central nervous system disease.
References: Smith ER, Zurakowski D, Saad A, Scott RM, Moses MA.
Urinary biomarkers predict brain tumor presence and response to therapy.
Clin Cancer Res. 2008 Apr 15;14(8):2378-86