DOI: 10.1158/1078-0432.ccr-07-4725. Impact of a Single Nucleotide Polymorphism in the <i>MDM2</i> Gene on Neuroblastoma Development and Aggressiveness: Results of a Pilot Study on 239 Patients

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

10.1158/1078-0432.ccr-07-4725

Crossref journal-article

American Association for Cancer Research (AACR)

Clinical Cancer Research (1086)

Abstract

Abstract Purpose: MDM2 is a key negative regulator of p53 activity, and a single nucleotide polymorphism (SNP309, T&gt;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 &gt;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.

Bibliography

Cattelani, S., Defferrari, R., Marsilio, S., Bussolari, R., Candini, O., Corradini, F., Ferrari-Amorotti, G., Guerzoni, C., Pecorari, L., Menin, C., Bertorelle, R., Altavista, P., McDowell, H. P., Boldrini, R., Dominici, C., Tonini, G. P., RaschellaÌ, G., & Calabretta, B. (2008). Impact of a Single Nucleotide Polymorphism in the MDM2 Gene on Neuroblastoma Development and Aggressiveness: Results of a Pilot Study on 239 Patients. Clinical Cancer Research, 14(11), 3248â3253.

Authors 18

Sara Cattelani (first)
Raffaella Defferrari (additional)
Sonia Marsilio (additional)
Rita Bussolari (additional)
Olivia Candini (additional)
Francesca Corradini (additional)
Giovanna Ferrari-Amorotti (additional)
Clara Guerzoni (additional)
Luisa Pecorari (additional)
Chiara Menin (additional)
Roberta Bertorelle (additional)
Pierluigi Altavista (additional)
Heather P. McDowell (additional)
Renata Boldrini (additional)
Carlo Dominici (additional)
Gian Paolo Tonini (additional)
Giuseppe Raschellà (additional)
Bruno Calabretta (additional)

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Shimada H, Ambros IM, Dehner LP, et al. The International Neuroblastoma Pathology Classification (the Shimada system). Cancer 1999;86:364–72. (10.1002/(SICI)1097-0142(19990715)86:2<364::AID-CNCR21>3.0.CO;2-7)
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Imamura J, Bartram CR, Berthold F, Harms D, Nakamura H, Koeffler HP. Mutation of the p53 gene in neuroblastoma and its relationship with N-myc amplification. Cancer Res 1993;53:4053–8.
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Dates

Type	When
Created	17 years, 2 months ago (June 2, 2008, 3:46 p.m.)
Deposited	3 years, 2 months ago (June 10, 2022, 10:38 p.m.)
Indexed	11 months, 2 weeks ago (Sept. 2, 2024, 7:12 a.m.)
Issued	17 years, 2 months ago (June 1, 2008)
Published	17 years, 2 months ago (June 1, 2008)
Published Online	17 years, 2 months ago (June 2, 2008)
Published Print	17 years, 2 months ago (June 1, 2008)

Funders 0

None

BibTeX

@article{Cattelani_2008, title={Impact of a Single Nucleotide Polymorphism in the MDM2 Gene on Neuroblastoma Development and Aggressiveness: Results of a Pilot Study on 239 Patients}, volume={14}, ISSN={1557-3265}, url={http://dx.doi.org/10.1158/1078-0432.ccr-07-4725}, DOI={10.1158/1078-0432.ccr-07-4725}, number={11}, journal={Clinical Cancer Research}, publisher={American Association for Cancer Research (AACR)}, author={Cattelani, Sara and Defferrari, Raffaella and Marsilio, Sonia and Bussolari, Rita and Candini, Olivia and Corradini, Francesca and Ferrari-Amorotti, Giovanna and Guerzoni, Clara and Pecorari, Luisa and Menin, Chiara and Bertorelle, Roberta and Altavista, Pierluigi and McDowell, Heather P. and Boldrini, Renata and Dominici, Carlo and Tonini, Gian Paolo and Raschellà, Giuseppe and Calabretta, Bruno}, year={2008}, month=jun, pages={3248–3253} }

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  "abstract": "<jats:title>Abstract</jats:title>\n               <jats:p>Purpose: MDM2 is a key negative regulator of p53 activity, and a single nucleotide polymorphism (SNP309, T&amp;gt;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.</jats:p>\n               <jats:p>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).</jats:p>\n               <jats:p>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 &amp;gt;1 year and adrenal primary tumor (P = 0.024 and P = 0.014, respectively).</jats:p>\n               <jats:p>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.</jats:p>",
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