[1879] MDM2 SNP-309 Promoter Polymorphism, MDM2 and p53 Expression in Pancreatic Ductal Adenocarcinoma

Xiaoping Zhou, Jonathan Rock, Megan E McNally, Mark Bloomston, Weiqiang Zhao, Gerard Lozanski, Wendy L Frankel. Ohio State Universcity, Columbus, OH

Background: The mouse double minute 2 homolog (MDM2) is the primary regulator of p53. A functional single nucleotide polymorphism (SNP) of the MDM2 promoter (309 T>G) enhances the Sp1 binding to MDM2 promoter and MDM2 expression resulting in attenuation of p53. Small molecules antagonizing the MDM2-p53 interaction have been shown to promote p53-dependent tumor regression in vitro. The MDM2 SNP-309 has been recently associated with the development and prognosis of a variety of tumors. We hypothesized that the MDM2 SNP-309 is associated with increased risk of pancreatic ductal adenocarcinoma (PDAC) and worse outcome.
Design: Genotyping of MDM2 SNP-309 was performed on genomic DNA extracted from benign lymph node tissue of 189 PDAC by PCR amplification flanking the corresponding promoter region followed by temperature gradient capillary electrophoresis and direct sequencing. Tissue microarrays of PDAC were constructed and immunohistochemically stained for MDM2 and p53. Expression intensity was scored as 0 (absent), 1+ (modest) or 2+ (high). In addition, FISH analysis for MDM2 amplification was done in 20 PDAC (15 with modest or high expression). We evaluated the association between MDM2 SNP-309 and the risk of PDAC using Cramer's V Test (with 100 controls). We also investigated the relationships between MDM2 SNP-309 genotype, MDM2 and p53 expression and tumor stage and survival time.
Results: The MDM2 SNP-309 genotypes of PDAC were statistically different from those of controls (P = 0.041). The frequency of the G allele in PDAC was significantly higher than that in controls (P = 0.002).

MDM2 SNP-309 Genotypes in PDAC and Controls
 PDAC (n = 189)Controls (n = 100)
G/G31 (16.3%)12 (12%)
T/G97 (51.3%)40 (40%)
T/T61 (32.1%)48 (48%)
PDAC, pancreatic ductal adenocarcinoma; P = 0.041

Modest to high levels of MDM2 expression were detected in 56 tumors (29.6%; 1+ in 25, 2+ in 31), and modest to high levels of p53 were detected in 102 (54%; 1+ in 31, 2+ in 71). MDM2 amplification was not detected in the 20 PDAC analyzed using FISH. No association was observed between MDM2 SNP-309 genotype, MDM2 and p53 expression level and tumor stage or survival time.
Conclusions: The G allele of MDM2 SNP-309 is associated with increased risk of PDAC. Modest to high expression levels of MDM2 and p53 are frequently present in PDAC. It is unlikely that MDM2 SNP-309 or amplification contributes to the high expression level of MDM2. Further investigations with rigorous design are warranted to assess the magnitude of risk of PDAC with MDM2 SNP-309 and the prognostic value of MDM2 and p53 expression.
Category: Pancreas

Monday, March 19, 2012 8:30 AM

Platform Session: Section G1, Monday Morning

 

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