Vesicular monoamine transporter protein expression correlates with clinical features, tumor biology, and MIBG avidity in neuroblastoma: a report from the Children's Oncology Group.
OBJECTIVE
Vesicular monoamine transporters 1 and 2 (VMAT1 and VMAT2) are thought to mediate MIBG uptake in adult neuroendocrine tumors. In neuroblastoma, the norepinephrine transporter (NET) has been investigated as the principal MIBG uptake protein, though some tumors without NET expression concentrate MIBG. We investigated VMAT expression in neuroblastoma and correlated expression with MIBG uptake and clinical features.


METHODS
We evaluated VMAT1 and VMAT2 expression by immunohistochemistry (IHC) in neuroblastoma tumors from 76 patients with high-risk metastatic disease treated in a uniform cooperative group trial (COG A3973). All patients had baseline MIBG diagnostic scans centrally reviewed. IHC results were scored as the product of intensity grading (0 - 3+) and percent of tumor cells expressing the protein of interest. The association between VMAT1 and VMAT2 scores and clinical and biological features was tested using Wilcoxon rank-sum tests.


RESULTS
Patient characteristics were typical of high-risk neuroblastoma, though the cohort was intentionally enriched in patients with MIBG-nonavid tumors (n = 20). VMAT1 and VMAT2 were expressed in 62% and 75% of neuroblastoma tumors, respectively. VMAT1 and VMAT2 scores were both significantly lower in MYCN amplified tumors and in tumors with high mitotic karyorrhectic index. MIBG-avid tumors had significantly higher VMAT2 scores than MIBG-nonavid tumors (median 216 vs. 45; p = 0.04). VMAT1 expression did not correlate with MIBG avidity.


CONCLUSIONS
VMAT1 and VMAT2 are expressed in the majority of neuroblastomas. Expression correlates with other biological features. The expression level of VMAT2 but not that of VMAT1 correlates with avidity for MIBG.
Department of Pediatrics, UCSF School of Medicine, San Francisco, CA 94143.|UCSF Benioff Children's Hospital, San Francisco, CA 94158.
William
W
Temple
Department of Pediatrics, UCSF School of Medicine, San Francisco, CA 94143.|UCSF Benioff Children's Hospital, San Francisco, CA 94158.
Lori
L
Mendelsohn
Department of Pathology, UCSF School of Medicine, San Francisco, CA 94143.
Grace E
GE
Kim
Department of Pediatrics, UCSF School of Medicine, San Francisco, CA 94143.|UCSF Benioff Children's Hospital, San Francisco, CA 94158.
Erin
E
Nekritz
Department of Pediatrics, UCSF School of Medicine, San Francisco, CA 94143.|UCSF Benioff Children's Hospital, San Francisco, CA 94158.
W Clay
WC
Gustafson
Department of Bioengineering and Therapeutic Sciences, UCSF School of Pharmacy, San Francisco, CA 94143.
Lawrence
L
Lin
Department of Bioengineering and Therapeutic Sciences, UCSF School of Pharmacy, San Francisco, CA 94143.
Kathy
K
Giacomini
Children's Oncology Group Statistics and Data Center, University of Florida, Gainesville, FL 32607.
Arlene
A
Naranjo
Children's Oncology Group Statistics and Data Center, University of Florida, Gainesville, FL 32607.
Collin
C
Van Ryn
CS Mott Children's Hospital, University of Michigan, Ann Arbor, MI 48109.
Gregory A
GA
Yanik
Duke University Medical Center, Durham, NC 27710.
Susan G
SG
Kreissman
Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Michael
M
Hogarty
Department of Pediatrics, UCSF School of Medicine, San Francisco, CA 94143.|UCSF Benioff Children's Hospital, San Francisco, CA 94158.
Katherine K
KK
Matthay
Department of Pediatrics, UCSF School of Medicine, San Francisco, CA 94143.|UCSF Benioff Children's Hospital, San Francisco, CA 94158.
Steven G
SG
DuBois
D019797:3-Iodobenzylguanidine / Q000737:chemistry*; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D009362:Neoplasm Metastasis; D009447:Neuroblastoma / Q000628:therapy*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D012189:Retrospective Studies; D016896:Treatment Outcome; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
D050484:Norepinephrine Plasma Membrane Transport Proteins; C493449:SLC18A1 protein, human; C493452:SLC18A2 protein, human; C493227:SLC6A2 protein, human; D050493:Vesicular Monoamine Transport Proteins; D019797:3-Iodobenzylguanidine
MIBG avidity; Neuroblastoma; VMAT1; VMAT2; Vesicular monoamine transporters