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Prognostic Significance of EZH2-Related Gene Variants in Patients With Prostate Cancer Undergoing Androgen Deprivation Therapy

SHU-PIN HUANG, BO-YING BAO, TA-HSIEN CHUANG, CHAO-YUAN HUANG, CHIA-CHENG YU, VICTOR C. LIN, TE-LING LU and YEI-TSUNG CHEN
Cancer Genomics & Proteomics July 2025, 22 (4) 611-623; DOI: https://doi.org/10.21873/cgp.20525
SHU-PIN HUANG
1Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.;
2Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, R.O.C.;
3Institute of Medical Science and Technology, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan, R.O.C.;
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BO-YING BAO
4Department of Pharmacy, China Medical University, Taichung, Taiwan, R.O.C.;
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TA-HSIEN CHUANG
4Department of Pharmacy, China Medical University, Taichung, Taiwan, R.O.C.;
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CHAO-YUAN HUANG
5Department of Urology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan, R.O.C.;
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CHIA-CHENG YU
6Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, R.O.C.;
7Department of Urology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, R.O.C.;
8Department of Pharmacy, College of Pharmacy and Health Care, Tajen University, Pingtung, Taiwan, R.O.C.;
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VICTOR C. LIN
9Department of Urology, E-Da Hospital, Kaohsiung, Taiwan, R.O.C.;
10School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan, R.O.C.;
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TE-LING LU
4Department of Pharmacy, China Medical University, Taichung, Taiwan, R.O.C.;
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YEI-TSUNG CHEN
11Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan, R.O.C.
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  • For correspondence: yeitsungchen{at}nycu.edu.tw
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    Figure 1.

    Manhattan plots depicting the association between 76 single-nucleotide polymorphisms (SNPs) across 10 EZH2-related genes and (A) cancer-specific survival and (B) overall survival in patients with prostate cancer undergoing androgen deprivation therapy. The Y-axis represents −log10(p) values, whereas the X-axis indicates chromosomal positions of the SNPs. The nominal significance threshold (p=0.05) (blue horizontal line marks). SNPs meeting the significance criteria (red circles).

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    Figure 2.

    Functional impact of DNMT3A rs77993651. (A) Regulatory annotations for rs77993651 derived from HaploReg. (B) Expression quantitative trait loci analysis demonstrates the relationship between rs77993651 and DNMT3A expression levels across various human tissues. The nominal significance threshold (p=0.05) (blue horizontal line marks). The negative (inverted triangle) and non-significant (circles) effects of rs77993651 on DNMT3A expression. Sample sizes for each subgroup (numbers in brackets).

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    Figure 3.

    Pooled analysis compares DNMT3A expression in normal versus prostate cancer tissues across 35 independent studies. DNMT3A levels are significantly elevated in prostate cancer samples. SD, standard deviation. IV, inverse variance. CI, confidence interval. Std, standardized. TCGA PRAD, The Cancer Genome Atlas Prostate Adenocarcinoma. df, Degrees of freedom.

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    Figure 4.

    Clinical relevance of DNMT3A expression in prostate cancer. Elevated DNMT3A expression is linked to poorer progression-free survival in datasets (A) GSE21032 and (B) The Cancer Genome Atlas prostate adenocarcinoma (TCGA PRAD). Additionally, DNMT3A levels are significantly higher in tumors with increased Gleason scores and advanced staging within the TCGA PRAD cohort. Sample sizes for each subgroup (numbers in brackets).

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    Figure 5.

    Gene ontology (GO) and pathway enrichment analyses of genes associated with DNMT3A expression. Top 10 GO terms are shown for (A) cellular components, (B) biological processes, and (C) molecular functions. (D) The most enriched Hallmark pathways. The ratio of core enrichment genes (bubble size) and its statistical significance (color scale).

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    Figure 6.

    Correlation between DNMT3A expression and key regulators of the G2/M checkpoint pathway in prostate cancer. The inverse relationship between DNMT3A and the methylation status of three hub genes: (A) AURKB, (B) CCNA2, and (C) CDK1 (left panel). The positive correlation between DNMT3A and the expression of these genes (middle-left panel). Elevated expressions of AURKB, CCNA2, and CDK1 in prostate cancer tissues relative to normal samples (middle-right panel). Higher expression levels of these genes are associated with worse survival outcomes in prostate cancer (right panel). Expression data were log2(x+1) transformed RNA sequencing by expectation-maximization normalized count. Patient groups were dichotomized into low- and high-expression categories based on the median expression value. Sample sizes for each subgroup (numbers in brackets).

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Cancer Genomics - Proteomics: 22 (4)
Cancer Genomics & Proteomics
Vol. 22, Issue 4
July-August 2025
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Prognostic Significance of EZH2-Related Gene Variants in Patients With Prostate Cancer Undergoing Androgen Deprivation Therapy
SHU-PIN HUANG, BO-YING BAO, TA-HSIEN CHUANG, CHAO-YUAN HUANG, CHIA-CHENG YU, VICTOR C. LIN, TE-LING LU, YEI-TSUNG CHEN
Cancer Genomics & Proteomics Jul 2025, 22 (4) 611-623; DOI: 10.21873/cgp.20525

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Prognostic Significance of EZH2-Related Gene Variants in Patients With Prostate Cancer Undergoing Androgen Deprivation Therapy
SHU-PIN HUANG, BO-YING BAO, TA-HSIEN CHUANG, CHAO-YUAN HUANG, CHIA-CHENG YU, VICTOR C. LIN, TE-LING LU, YEI-TSUNG CHEN
Cancer Genomics & Proteomics Jul 2025, 22 (4) 611-623; DOI: 10.21873/cgp.20525
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Keywords

  • prostate cancer
  • EZH2
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  • gene set enrichment analysis
  • survival
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