Using urinary bFGF and TIMP3 levels to predict the presence of juvenile pilocytic astrocytoma and establish a distinct biomarker signature

Abstract

<jats:sec> <jats:title>OBJECTIVE</jats:title> <jats:p>The authors report the use of urinary biomarkers as a novel, noninvasive technique to detect juvenile pilocytic astrocytomas (JPAs), capable of distinguishing JPAs from other CNS diseases, including other brain tumors. Preliminary screening of an array of tumors implicated proteases (including matrix metalloproteinases [MMPs]) and their inhibitors (tissue inhibitors of metalloproteinase [TIMPs]) as well as growth factors (including basic fibroblast growth factor [bFGF]) as candidate biomarkers. These data led the authors to hypothesize that tissue inhibitor of metalloproteinase 3 (TIMP3) and bFGF would represent high-probability candidates as JPA-specific biomarkers.</jats:p></jats:sec> <jats:sec> <jats:title>METHODS</jats:title> <jats:p>Urine was collected from 107 patients, which included children with JPA (n = 21), medulloblastoma (n = 17), glioblastoma (n = 9), arteriovenous malformations (n = 25), moyamoya (n = 14), and age- and sex-matched controls (n = 21). Biomarker levels were quantified with enzyme-linked immunosorbent assay, tumor tissue expression was confirmed with immunohistochemical analysis, and longitudinal biomarker expression was correlated with imaging. Results were subjected to univariate and multivariate statistical analyses.</jats:p></jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p>Using optimal urinary cutoff values of bFGF &gt; 1.0 pg/μg and TIMP3 &gt; 3.5 pg/μg, multiplexing bFGF and TIMP3 predicts JPA presence with 98% accuracy. Multiplexing bFGF and MMP13 distinguishes JPA from other brain tumor subtypes with up to 98% accuracy. Urinary biomarker expression correlated with both tumor immunohistochemistry and in vitro tumor levels. Urinary bFGF and TIMP3 decrease following successful tumor treatment and correlate with changes in tumor size.</jats:p></jats:sec> <jats:sec> <jats:title>CONCLUSIONS</jats:title> <jats:p>This study identifies 2 urinary biomarkers—bFGF and TIMP3—that successfully detect one of the most common pediatric brain tumors with high accuracy. These data highlight potential benefits of urinary biomarkers and support their utility as diagnostic tools in the treatment of children with JPA.</jats:p></jats:sec>

Dysregulation of the EphrinB2−EphB4 ratio in pediatric cerebral arteriovenous malformations is associated with endothelial cell dysfunction in vitro and functions as a novel noninvasive biomarker in patients

“…Tissue and urine specimens were collected as previously published 21,23 in accordance with protocols approved by the Boston Children's Hospital IRB (IRB#10-417); informed consent was obtained. Only patients with magnetic resonance imaging (MRI) of the central nervous system were included.…”

“…As previously reported by our group and in accordance with an IRB-approved protocol, urine samples were collected preoperatively between 2006 and 2014 21,[23][24][25] . No patient had evidence of other major physiologic stressors, such as stroke, recent surgery, chemotherapy or radiation, at the time of collection.…”

“…024841, Salem, MA). Assays were performed per company protocol after determining the urine protein concentration by Bradford assay, as previously reported 21,[23][24][25] .…”

Metalloproteinases and their roles in human cancer

“…Along with MMPs, urinary TIMPs have also been evaluated as potential biomarkers for juvenile pilocytic astrocytoma (JPA). Multiplexing urinary TIMP‐3 with bFGF could distinguish JPA patients from controls (Pricola Fehnel et al, ). This study found that urinary TIMP‐3 could be a promising biomarker of JPA progression when compared to patients' baseline levels (Pricola Fehnel et al, ).…”

“…Multiplexing urinary TIMP‐3 with bFGF could distinguish JPA patients from controls (Pricola Fehnel et al, ). This study found that urinary TIMP‐3 could be a promising biomarker of JPA progression when compared to patients' baseline levels (Pricola Fehnel et al, ). In the same study, multiplexing urinary MMP‐13 with bFGF also accurately distinguished JPA from medulloblastoma, a more aggressive tumor compared to JPA (Pricola Fehnel et al, ).…”