MDM2 Promoter Polymorphism and Pancreatic Cancer Risk and Prognosis

• Published in: Clinical cancer research 2008-06, Vol.14 (12), p.4010-4015
• Main Authors: ASOMANING, Kofi, REID, Amy E, CHRISTIANI, David C, LIU, Geoffrey, WEI ZHOU, HEIST, Rebecca S, RIHONG ZHAI, LI SU, KWAK, Eunice L, BLASZKOWSKY, Lawrence, ZHU, Andrew X, RYAN, David P
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - diagnosis; Adenocarcinoma - genetics; Adenocarcinoma - mortality; Adult; Aged; Aged, 80 and over; Antineoplastic agents; Biological and medical sciences; Case-Control Studies; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genetic Predisposition to Disease; Humans; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; MDM2; Medical sciences; Middle Aged; overall survival; pancreatic cancer; Pancreatic Neoplasms - diagnosis; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - mortality; Pharmacology. Drug treatments; Polymorphism, Genetic; Prognosis; progression-free survival; Promoter Regions, Genetic; Proto-Oncogene Proteins c-mdm2 - genetics; Risk; Survival Analysis; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-4187

Purpose: The mouse double minute 2 homologue ( MDM2 ) -309T/G promoter polymorphism has been associated recently with the development and prognosis of a variety of tumors. The G allele is associated with increased affinity for Sp1 binding and higher MDM2 mRNA and protein levels, leading to diminished tumor suppressor activity of the p53 pathway. We hypothesized that the G allele is also associated with increased risk and worse outcome in pancreatic cancer. Experimental Design: We evaluated the association between MDM2 309T/G and the risk of histologically confirmed pancreatic adenocarcinoma at Massachusetts General Hospital using unconditional logistic regression (123 cases and 372 controls). Complete overall survival and progression-free survival data were also available for 109 newly diagnosed patients. Results: The adjusted odds ratios (95% confidence intervals) of pancreatic cancer associated with the MDM2 T/G and G/G genotypes compared with TT were 1.89 (1.20-2.99) and 2.07 (1.03-4.16), respectively (adjusting for age, gender, smoking status, and pack-years of smoking). In Cox proportional hazards model with the wild-type T/T genotype as the reference category and adjusting for stage, treatment, and performance status, both the heterozygous T/G and the homozygous G/G genotypes were associated with decreased progression-free survival [adjusted hazard ratio (95% confidence interval), 1.67 (0.98-2.84) for T/G and 2.28 (1.11-4.71) for G/G ] and overall survival [2.64 (1.23-5.67) for T/G and 3.12 (1.22-7.91) for G/G ]. Conclusions: The G allele of the MDM2 -309T/G polymorphism is associated with 2- to 3-fold increase risk and progression of pancreatic adenocarcinoma and a corresponding decrease in survival.