Genetic variations in TP53 binding sites are predictors of clinical outcomes in prostate cancer patients.
Since the tumor protein p53 (TP53), a transcription factor, plays a crucial role in prostate cancer development and progression, we hypothesized that sequence variants in TP53 binding sites might affect clinical outcomes in patients with prostate cancer. We systematically evaluated 41 single nucleotide polymorphisms (SNPs) within genome-wide predicted TP53 binding sites in a cohort of 1,024 prostate cancer patients. The associations of these SNPs with prostate cancer characteristics and clinical outcomes after radical prostatectomy for localized disease and after androgen-deprivation therapy (ADT) for advanced disease were assessed by Kaplan-Meier analysis and Cox regression model. ARAP2 rs1444377 and TRPS1 rs722740 were associated with advanced stage prostate cancer. FRK rs171866 remained as a significant predictor for disease progression; DAB2 rs268091 and EXOC4 rs1149558 remained as significant predictors for prostate cancer-specific mortality (PCSM); and EXOC4 rs1149558 remained as a significant predictor for all-cause mortality after ADT in multivariate models that included clinicopathologic predictors. In addition, the numbers of protective genotypes at DAB2 rs268091 and EXOC4 rs1149558 showed a cumulative effect on PCSM (P for trend = 0.002). Our results suggested that SNPs within TP53 binding sites might be valuable biomarkers for prostate cancer outcome prediction.
Department of Urology, E-Da Hospital, Kaohsiung, Taiwan.
Victor C
VC
Lin
Chao-Yuan
CY
Huang
Yung-Chin
YC
Lee
Chia-Cheng
CC
Yu
Ta-Yuan
TY
Chang
Te-Ling
TL
Lu
Shu-Pin
SP
Huang
Bo-Ying
BY
Bao
D000726:Androgen Antagonists / Q000627:therapeutic use; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000235:genetics*; D045744:Cell Line, Tumor; D018450:Disease Progression; D018572:Disease-Free Survival; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000628:therapy; D065840:Protective Factors; D012307:Risk Factors; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000726:Androgen Antagonists; D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53