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Genetic variations in TP53 binding sites are predictors of clinical outcomes in prostate cancer patients

  • Toxicogenomics
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Abstract

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.

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Abbreviations

SNP:

Single nucleotide polymorphism

RP:

Radical prostatectomy

ADT:

Androgen-deprivation therapy

PCSM:

Prostate cancer-specific mortality

ACM:

All-cause mortality

PSA:

Prostate-specific antigen

OR:

Odds ratio

95 % CI:

95 % confidence interval

HR:

Hazard ratio

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Acknowledgments

This work was supported by grants from the National Science Council (NSC), Taiwan (NSC-98-2320-B-039-019-MY3, NSC-100-2314-B-039-009-MY3, and NSC-102-2628-B-039-005-MY3) and Kaohsiung Medical University Hospital (KMUH100-0R42). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We also thank Chao-Shih Chen for data analysis and the National Center for Genome Medicine, NSC, Taiwan, for technical support.

Conflict of interest

The authors declare no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Urology, E-Da Hospital, Kaohsiung, Taiwan

    Victor C. Lin

  2. Department of Nursing, I-Shou University, Kaohsiung, Taiwan

    Victor C. Lin

  3. Department of Urology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan

    Chao-Yuan Huang

  4. Department of Urology, Kaohsiung Medical University Hospital, 100 Ziyou 1st Road, Kaohsiung, 807, Taiwan

    Yung-Chin Lee & Shu-Pin Huang

  5. Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Yung-Chin Lee & Shu-Pin Huang

  6. Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

    Chia-Cheng Yu

  7. Department of Urology, School of Medicine, National Yang-Ming University, Taipei, Taiwan

    Chia-Cheng Yu

  8. Department of Pharmacy, Tajen University, Pingtung, Taiwan

    Chia-Cheng Yu

  9. Department of Occupational Safety and Health, China Medical University, Taichung, Taiwan

    Ta-Yuan Chang

  10. Department of Pharmacy, China Medical University, 91 Xueshi Road, Taichung, 404, Taiwan

    Te-Ling Lu & Bo-Ying Bao

  11. Sex Hormone Research Center, China Medical University Hospital, Taichung, Taiwan

    Bo-Ying Bao

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  1. Victor C. Lin
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Corresponding authors

Correspondence to Shu-Pin Huang or Bo-Ying Bao.

Additional information

Victor C. Lin and Chao-Yuan Huang contributed equally to this work.

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Lin, V.C., Huang, CY., Lee, YC. et al. Genetic variations in TP53 binding sites are predictors of clinical outcomes in prostate cancer patients. Arch Toxicol 88, 901–911 (2014). https://doi.org/10.1007/s00204-014-1196-8

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  • DOI: https://doi.org/10.1007/s00204-014-1196-8

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