Evaluation of Norepinephrine Transporter Expression and Metaiodobenzylguanidine Avidity in Neuroblastoma: A Report from the Children's Oncology Group

Steven G Dubois,John Neuhaus,Sook Wah Yee,Wendy B London,Greg Yanik,Susan Kreissman,Arlene Naranjo,Ethan Geier,Bruce Pawel,John M Maris,Vandana Batra,David Baker,Kathleen Giacomini,Daniel Martinez,Edward Attiyeh,Katherine K Matthay,Michael D Hogarty,Mark Segal

doi:10.1155/2012/250834

Abstract

Purpose. 123I-metaiodobenzylguanidine (MIBG) is used for the diagnostic evaluation of neuroblastoma. We evaluated the relationship between norepinephrine transporter (NET) expression and clinical MIBG uptake. Methods. Quantitative reverse transcription PCR (N = 82) and immunohistochemistry (IHC; N = 61) were performed for neuroblastoma NET mRNA and protein expression and correlated with MIBG avidity on diagnostic scans. The correlation of NET expression with clinical features was also performed. Results. Median NET mRNA expression level for the 19 MIBG avid patients was 12.9% (range 1.6–73.7%) versus 5.9% (range 0.6–110.0%) for the 8 nonavid patients (P = 0.31). Median percent NET protein expression was 50% (range 0–100%) in MIBG avid patients compared to 10% (range 0–80%) in nonavid patients (P = 0.027). MYCN amplified tumors had lower NET protein expression compared to nonamplified tumors (10% versus 50%; P = 0.0002). Conclusions. NET protein expression in neuroblastoma correlates with MIBG avidity. MYCN amplified tumors have lower NET protein expression.

Highlights

Metaiodobenzylguanidine (MIBG) is an agent that is taken up by sympathetic nervous system tissues, including neuroblastoma tumors. 123I-MIBG plays an essential role in the diagnostic evaluation of patients with neuroblastoma [1]
Additional studies in neuroblastoma and other neuroendocrine tumors have suggested that vesicular monoamine transporters (VMATs) and organic cation transporters (OCTs) may play a role in mediating uptake of MIBG [18,19,20]
norepinephrine transporter (NET) mRNA expression correlated with MIBG avidity, we evaluated whether NET protein expression correlated with clinical MIBG avidity

Summary

Introduction

Metaiodobenzylguanidine (MIBG) is an agent that is taken up by sympathetic nervous system tissues, including neuroblastoma tumors. 123I-MIBG plays an essential role in the diagnostic evaluation of patients with neuroblastoma [1]. 123I-MIBG plays an essential role in the diagnostic evaluation of patients with neuroblastoma [1]. The norepinephrine transporter (NET; encoded by SLC6A2 gene) is thought to be the primary transporter responsible for specific active cellular uptake of MIBG [3]. A range of cells that do not typically accumulate MIBG can be engineered to do so by transfection of the NET gene [9,10,11,12,13,14,15,16,17]. Additional studies in neuroblastoma and other neuroendocrine tumors have suggested that vesicular monoamine transporters (VMATs) and organic cation transporters (OCTs) may play a role in mediating uptake of MIBG [18,19,20]

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Conclusion