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Impact of a Single Nucleotide Polymorphism in the MDM2 Gene on Neuroblastoma Development and Aggressiveness: Results of a Pilot Study on 239 Patients

Authors' Affiliations: Departments of ¹ Biomedical Sciences and ² Oncology and Hematology, Modena and Reggio Emilia University, Modena, Italy; ³ Laboratory of Neuroblastoma Research, Italian Neuroblastoma Foundation and ⁴ Translational Pediatric Oncology, National Institute for Cancer Research, Genoa, Italy; ⁵ Department of Pediatrics, La Sapienza University, ⁶ Section of Toxicology and Biomedical Sciences, Ente per le Nuove tecnologie l'Energia e l'Ambiente, Research Center Casaccia, ⁷ Division of Pathology, and ⁸ Laboratory of Oncology, Bambin Gesù Children's Hospital, Rome, Italy; ⁹ Molecular Immunology and Diagnostic Oncology, Istituto Oncologico Veneto, Interdisciplinary Research Chair in Surface Science, Padova, Italy; ¹⁰ Department of Oncology, Royal Liverpool Children's NHS Trust Alder Hey and ¹¹ Division of Child Health, School of Reproductive and Developmental Medicine, Liverpool University, Liverpool, United Kingdom; and ¹² Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania

Requests for reprints: Bruno Calabretta, Kimmel Cancer Center, 233 South 10th street, Philadelphia, PA 19107. Phone: 001-215-503-4522; Fax: 001-215-923-9248; E-mail: B_Calabretta{at}mail.jci.tju.edu.

Purpose: MDM2 is a key negative regulator of p53 activity, and a single nucleotide polymorphism (SNP309, T>G change; rs 2279744) in its promoter increases the affinity for the transcription factor SP1, enhancing MDM2 expression. We carried out a pilot study to investigate the effect of this polymorphism on development and behavior of neuroblastoma, an extracranial pediatric tumor with unfrequent genetic inactivation of p53.

Experimental Design: We genotyped the MDM2-SNP309 alleles of tumor DNA from 239 neuroblastoma patients and peripheral blood DNA from 237 controls. In 40 of 239 neuroblastomas, the MDM2-SNP309 alleles were also genotyped in peripheral blood DNA. Data were analyzed by two-sided Fisher's exact test, log-rank test, and Kaplan-Meier statistics. Where appropriate, data are reported with 95% confidence intervals (CI).

Results: The frequency of both the T/G and G/G genotypes or the G/G or T/G genotype only was higher in neuroblastoma DNA samples than in controls: 60.3% (95% CI, 54.1-66.5) versus 47.3% (95% CI, 40.9-53.6), 30.4% (95% CI, 22.4-37.8) versus 15.0% (95% CI, 9.2-20.7), and 52.0% (95% CI, 45.0-59.9) versus 41.9% (95% CI, 35.3-48.5), respectively; Two-Sided Fisher's Exact Test P values were 0.006, 0.003, and 0.048, respectively; Odds ratios were 1.69 (95% CI, 1.18-2.43), 2.45 (95% CI, 1.37-4.39) and 1.51 (95% CI, 1.02-2.22), respectively. A significant association (P = 0.016) between heterozygous (T/G)/homozygous (G/G) genotypes at SNP309 and advanced clinical stages was also shown. Homozygous/heterozygous SNP309 variant carriers had a shorter 5-year overall survival than patients with the wild-type allele (P = 0.046; log-rank test). A shorter overall survival in patients with heterozygous/homozygous SNP309 was also observed in the subgroups with age at diagnosis >1 year and adrenal primary tumor (P = 0.024 and P = 0.014, respectively).

Conclusions: Data from this pilot study suggest that the MDM2 G/G and T/G-SNP309 alleles are markers of increased predisposition to tumor development and disease aggressiveness in neuroblastoma. However, additional studies with larger patient cohorts are required for a definitive assessment of the clinical relevance of these data.

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