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GABAergic System Gene Expression Predicts Clinical Outcome in Patients With Neuroblastoma

From the Center for Biomarker Discovery, Division of Pediatric Hematology/Oncology, Department of Pediatrics, Division of Biostatistics, Department of Public Health and Preventive Medicine, Oregon Health & Science University, Portland, OR; Children's Center for Cancer and Blood Diseases, Children's Hospital, Los Angeles; and Children's Cancer Group, Arcadia, CA

Address reprint requests to Srinivasa R. Nagalla, MD, Department of Pediatrics, NRC-5, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239; e-mail: nagallas{at}ohsu.edu

PURPOSE: Neuroblastoma (NB) is a common childhood malignancy characterized by heterogeneous clinical behavior. The purpose of this study was to identify potential NB biomarkers that may improve outcome prediction.

PATIENTS AND METHODS: The suppression subtractive hybridization (SSH) technique was used to identify the genes differentially expressed between NB and control tissue. RNA isolated from 235 primary NB tumor samples obtained from the Children's Cancer Group was evaluated for expression of the candidate markers using quantitative reverse transcriptase polymerase chain reaction (Taqman assays). The association between the mRNA expression levels in the identified candidate genes and clinical outcome was evaluated.

RESULTS: SSH analysis identified differential expression of members of the GABAergic gene family in NB. Lower levels of gamma-aminobutyric acid (GABA) receptor–associated protein (GABARAP) gene expression predict decreased survival among all patients. GABA_A receptor subunit gene expression was predictive of a poor outcome among Evans stage IV-S patients. An index of five coexpressed GABA_A receptor subunits was identified (GABA_A profile [GAP score]). Patients with a higher GAP score (> –1) had a survival advantage. Multivariate analysis showed that GABARAP and GABA_A 2 receptor subunit gene expression levels and GAP score remained predictors of clinical outcome after accounting for current prognostic indicators.

CONCLUSION: Dysregulation of the GABAergic system may constitute a fundamental event in the development of NB, and assessment of GABAergic system gene expression could provide improved patient stratification and potential new therapies.

Supported in part by grants from the National Cancer Institute, The Lematta Foundation, and The Dickinson Foundation to S.R.N. Additional support was received from the Biostatistics & Bioinformatics Shared Resource of the Oregon Health & Science University Cancer Institute (NCI CCSG: 5P30 CA69533-04).

Presented in part at the Children's Oncology Group Neuroblastoma Biology Committee meeting, October 2002, St Louis, MO, and the American Association for Cancer Research Annual Meeting, July 12, 2003, Washington, DC.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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