p53 Arg72Pro and MDM2 T309G polymorphisms, histology, and esophageal cancer prognosis.
OBJECTIVE
This study aimed to evaluate the prognostic significance of two functional single nucleotide polymorphisms (SNP) in the p53 pathway (p53 Arg72Pro and MDM2 T309G) in patients with esophageal cancer, and to determine the importance of histologic subtype in the SNP-outcome relationships.


METHODS
A cohort of 371 patients with esophageal carcinoma enrolled in Boston, USA from 1999 to 2004 were genotyped for the p53 and MDM2 SNPs. Associations between genotypes and overall survival (OS; the primary outcome) and progression-free survival (PFS) were assessed using the Kaplan-Meier method. Cox proportional hazard models, adjusted for age, stage, performance status, and smoking were developed. Interaction analyses were done for histology (adenocarcinoma versus squamous cell carcinoma).


RESULTS
At the median follow-up of 33 months, median survival (MS) and PFS were 29.1 and 15.7 months, respectively. p53 Pro/Pro was strongly associated with shorter survival in the entire cohort (MS of 11.8 versus 29.1 months, P < 0.0001; adjusted hazard ratio for death, 2.05; 95% confidence interval, 1.30-3.24; P = 0.002 for Pro/Pro versus Arg/Arg). MDM2 G/G was associated with markedly reduced survival in squamous cell carcinoma (MS of 10.3 versus 49.4 months; adjusted hazard ratio for death, 7.9; 95% confidence interval, 2.4-26.0; P = 0.0007 for G/G versus T/T) but not in adenocarcinoma (SNP-histology interaction P = 0.004).


CONCLUSIONS
In a large prospective cohort, p53 Arg72Pro Pro/Pro was associated with a 2-fold increased risk of death in all esophageal cancers, whereas MDM2 T309G G/G was associated with a 7-fold increased risk of death in squamous cell carcinoma.
Cescon
David W
DW
Department of Medical Biophysics, Princess Margaret Hospital, University of Toronto, Canada.
Bradbury
Penelope A
PA
Asomaning
Kofi
K
Hopkins
Jessica
J
Zhai
Rihong
R
Zhou
Wei
W
Wang
Zhaoxi
Z
Kulke
Matthew
M
Su
Li
L
Ma
Clement
C
Xu
Wei
W
Marshall
Ariela L
AL
Heist
Rebecca Suk
RS
Wain
John C
JC
Lynch
Thomas J
TJ
Christiani
David C
DC
Liu
Geoffrey
G
D000230:Adenocarcinoma / Q000235:genetics* / Q000556:secondary / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000737:chemistry / Q000235:genetics; D001900:Boston; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000556:secondary / Q000628:therapy; D002454:Cell Differentiation; D015331:Cohort Studies; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011392:Proline / Q000737:chemistry / Q000235:genetics; D011446:Prospective Studies; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D055815:Young Adult
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D001120:Arginine; D011392:Proline; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2