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MDM2 promoter polymorphism and pancreatic cancer risk and prognosis
Kofi Asomaning1, Amy E Reid, Wei Zhou
1Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA.
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.
Insights
The mouse double minute 2 homologue (MDM2) -309T/G polymorphism
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- The MDM2 -309T/G promoter polymorphism influences MDM2 gene expression.
- The G allele is linked to higher MDM2 levels and reduced p53 tumor suppressor activity.
- This polymorphism has been implicated in various tumor types.
Purpose of the Study:
- To investigate the association between the MDM2 -309T/G polymorphism and pancreatic cancer risk.
- To evaluate the impact of this polymorphism on patient survival outcomes.
Main Methods:
- Case-control study of 123 pancreatic adenocarcinoma cases and 372 controls.
- Unconditional logistic regression used to assess risk.
- Cox proportional hazards models analyzed survival data for 109 patients.
Main Results:
- The MDM2 G allele (T/G and G/G genotypes) was associated with a 1.89- to 2.07-fold increased risk of pancreatic cancer.
- Both T/G and G/G genotypes correlated with decreased progression-free survival (HR 1.67-2.28) and overall survival (HR 2.64-3.12).
Conclusions:
- The G allele of the MDM2 -309T/G polymorphism significantly increases pancreatic cancer risk.
- This genetic variant is associated with poorer survival outcomes in pancreatic cancer patients.
