MDM2 promoter polymorphism and pancreatic cancer risk and prognosis.
OBJECTIVE
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.


METHODS
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.
Asomaning
Kofi
K
Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA.
Reid
Amy E
AE
Zhou
Wei
W
Heist
Rebecca S
RS
Zhai
Rihong
R
Su
Li
L
Kwak
Eunice L
EL
Blaszkowsky
Lawrence
L
Zhu
Andrew X
AX
Ryan
David P
DP
Christiani
David C
DC
Liu
Geoffrey
G
D000230:Adenocarcinoma / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D011110:Polymorphism, Genetic; D011379:Prognosis; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D012306:Risk; D016019:Survival Analysis
C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2