Using urinary bFGF and TIMP3 levels to predict the presence of juvenile pilocytic astrocytoma and establish a distinct biomarker signature.
OBJECTIVE 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. METHODS 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. RESULTS Using optimal urinary cutoff values of bFGF > 1.0 pg/μg and TIMP3 > 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. CONCLUSIONS 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.
Vascular Biology Program, and.|Departments of 2 Neurosurgery and.|Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts.
Katie
K
Pricola Fehnel
Vascular Biology Program, and.|Departments of 2 Neurosurgery and.
Micah
M
Duggins-Warf
Surgery, Boston Children's Hospital; and.
David
D
Zurakowski
Vascular Biology Program, and.|Departments of 2 Neurosurgery and.
Maxwell
M
McKee-Proctor
Vascular Biology Program, and.|Departments of 2 Neurosurgery and.
Rajarshi
R
Majumder
Vascular Biology Program, and.|Departments of 2 Neurosurgery and.
Michael
M
Raber
Vascular Biology Program, and.|Departments of 2 Neurosurgery and.
Xuezhe
X
Han
Vascular Biology Program, and.|Departments of 2 Neurosurgery and.
Edward R
ER
Smith
D001165:Arteriovenous Malformations / Q000652:urine; D001254:Astrocytoma / Q000652:urine*; D014408:Biomarkers, Tumor / Q000652:urine; D001932:Brain Neoplasms / Q000652:urine*; D045744:Cell Line, Tumor; D002648:Child; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000652:urine*; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000652:urine; D008527:Medulloblastoma / Q000652:urine; D009072:Moyamoya Disease / Q000652:urine; D015999:Multivariate Analysis; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000652:urine*
D014408:Biomarkers, Tumor; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D016222:Fibroblast Growth Factor 2; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13
AUC = area under the curve; AVM = arteriovenous malformation; CI = confidence interval; DAPI = 4,6′-diamino-2-phenylindole-dihydrochloride; DMEM = Dulbecco's modified Eagle's medium; EGF = epidermal growth factor; IQR = interquartile range; IRB = Institutional Review Board; JPA = juvenile pilocytic astrocytoma; MMP = matrix metalloproteinase; NF1 = neurofibromatosis Type 1; PBS = phosphate-buffered saline; ROC = receiver operating characteristic; TIMP3; TIMP3 = tissue inhibitor of metalloproteinase 3; VEGF = vascular endothelial growth factor; bFGF; bFGF = basic fibroblast growth factor; basic fibroblast growth factor; oncology; pilocytic astrocytoma; tissue inhibitor of metalloproteinase 3; urinary biomarkers