Genetic variants in nuclear factor-kappa B binding sites are associated with clinical outcomes in prostate cancer patients.
Nuclear factor-kappa B (NF-κB) transcription factors have been suggested to be involved in prostate cancer progression. Activated NF-κB translocates to the nucleus, binds to NF-κB binding sites and regulates target gene expression, leading to the given physiological response. It was hypothesised that the sequence variants in NF-κB binding sites might affect prostate cancer progression. We systematically evaluated 15 single-nucleotide polymorphisms (SNPs) within NF-κB binding sites those were predicted using a genome-wide database in a cohort of 1024 prostate cancer patients. Associations of these SNPs with prostate cancer characteristics and clinical outcomes after radical prostatectomy (RP) for localised disease, and after androgen-deprivation therapy (ADT) for advanced disease were assessed by Kaplan-Meier analysis and Cox regression model. We found that PSMD7 rs2387084 and MYCN rs1429409 were significantly related to earlier onset of prostate cancer and advanced clinical stage, respectively. No SNPs were significantly associated with disease recurrence after RP. Four and three SNPs were notably associated with prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM), respectively, after ADT. LSAMP rs13088089, CCL17 rs223899, PSMD7 rs2387084 and MON1B rs284924 remained the significant predictors for PCSM whilst PSMD7 rs2387084 remained a significant predictor for ACM in multivariate models including clinical predictors. Moreover, we also noted that there were strong effects of the combined genotype on PCSM and patients with a greater number of unfavourable genotypes had a shorter time to PCSM during ADT (P for trend<0.001). It was concluded that SNPs inside NF-κB binding sites might be useful to improve outcome prediction in prostate cancer patients.
Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Shu-Pin
SP
Huang
Victor C
VC
Lin
Yung-Chin
YC
Lee
Chia-Cheng
CC
Yu
Chao-Yuan
CY
Huang
Ta-Yuan
TY
Chang
Hong-Zin
HZ
Lee
Shin-Hun
SH
Juang
Te-Ling
TL
Lu
Bo-Ying
BY
Bao
D000368:Aged; D001665:Binding Sites / Q000235:genetics; D015331:Cohort Studies; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D000071447:N-Myc Proto-Oncogene Protein; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000401:mortality; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D011485:Protein Binding / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D016328:NF-kappa B; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C488765:PSMD7 protein, human; D046988:Proteasome Endopeptidase Complex
NF-κB; Outcomes; Prostate cancer; Single-nucleotide polymorphism