Single-nucleotide polymorphisms in p53 pathway and aggressiveness of prostate cancer in a Caucasian population.
OBJECTIVE
The tumor suppressor p53 plays a crucial role in maintaining genomic stability and tumor prevention. Mdm2, Mdm4, and Hausp are all critical regulators of the p53 protein. Despite the importance of the p53 pathway in prostate cancer development and progression, little is known about the association of functional single-nucleotide polymorphisms (SNP) in the p53 pathway genes and prostate cancer aggressiveness.


METHODS
In this study, we analyze the association of SNPs in p53, Mdm2, Mdm4, and Hausp genes with prostate cancer clinicopathologic variables in a large hospital-based Caucasian prostate cancer cohort (N = 4,073).


RESULTS
We found that the Mdm2 SNP309 T allele was associated with earlier onset prostate cancer (P = 0.004), higher Gleason scores (P = 0.004), and higher stages in men undergoing a radical prostatectomy (P = 0.011). Both the Mdm4 and Hausp SNPs (rs1380576 and rs1529916) were found to be associated with higher D'Amico risk prostate cancer category at the time of diagnosis (P = 0.023 and P = 0.046, respectively). Mdm4 SNP was also found to be associated with higher Gleason score at radical prostatectomy (P = 0.047). We did not observe any statistically significant association between the p53 Arg72Pro polymorphism and prostate cancer aggressiveness or pathologic variables.


CONCLUSIONS
These results suggested the importance of these p53 regulators in prostate cancer development and progression.
Sun
Tong
T
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Lee
Gwo-Shu Mary
GS
Oh
William K
WK
Pomerantz
Mark
M
Yang
Ming
M
Xie
Wanling
W
Freedman
Matthew L
ML
Kantoff
Philip W
PW
D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D018797:Cell Cycle Proteins; D015331:Cohort Studies; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D000076084:Ubiquitin-Specific Peptidase 7; D044465:White People / Q000235:genetics*
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7