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. 2025 Apr 8:15:1541878.
doi: 10.3389/fonc.2025.1541878. eCollection 2025.

5hmC-profiles in Puerto Rican Hispanic/Latino men with aggressive prostate cancer

Manishkumar S Patel  1 , Mousa Almubarak  1 , Jaime Matta  2 , Carmen Ortiz-Sanchez  2 , Jarline Encarnacion  2 , Gilberto Ruiz-Deya  2 , Julie Dutil  2 , Jasreman Dhillon  3 , Kosj Yamoah  4 , Anders Berglund  5 , Hyun Park  6 , Deepak Kilari  7 , Yoganand Balagurunathan  8 , Liang Wang #  1 , Jong Y Park #  6
Affiliations

5hmC-profiles in Puerto Rican Hispanic/Latino men with aggressive prostate cancer

Manishkumar S Patel et al. Front Oncol. .

Abstract

Introduction: Puerto Rican (PR) Hispanic/Latino (H/L) men are an understudied population that has the highest prostate cancer (PCa) specific mortality among other Hispanic populations. Little information is known about the higher mortality in PR H/L men. It is thought that epigenetic changes in key genes may play a critical role in aggressive tumors.

Methods: We aimed to identify key 5-hydroxymethylcytosine (5hmC) changes in PR H/L men with aggressive PCa. We performed sequencing analysis using the 5hmC-enriched DNA from 22 prostate tumors and 24 adjacent normal FFPE samples.

Results: We identified 808 differentially methylated genes (DMGs) in tumors compared to adjacent normal tissues. These genes suggest key mechanisms, including upregulated signatures of negative Androgen Receptor (AR) regulation, Wnt/β-catenin pathway activation, and downregulation of tumor suppressor genes. Pathway analysis of DMGs demonstrated that DNA repair pathway was most upregulated in tumors. Since 5hmC abundance positively correlates with gene expression levels, we further investigated 808 DMGs in TCGA PCa gene expression data. Further, we identified 59 DMGs with significant gene expression changes in the same direction. Additionally, we identified 111 aggressiveness-related DMGs, of which, two hypomethylated genes (CCDC122, NUDT15) and four hypermethylated genes (PVT1, RPL30, TRMT12, UBR5) were found to be altered at transcriptomic level in a concordant manner in PR H/L PCa patients. Aberrant 5hmC and GE changes in these six genes were also associated with progression-free survival in the mixed PCa population.

Discussion: The 5hmC modifications and associated gene expression changes in these six genes could be linked to the highest prostate cancer (PCa)-specific mortality in PR H/L men. In conclusion, our study identified 59 DMGs showing concordant epigenetic and transcriptomic changes in tumor tissues and 111 DMGs showing association with aggressive PCa among PR H/L men. Our findings have significant implications for understanding these key genes' molecular mechanisms, which may drive PCa progression and mortality in this population. This will help in developing potential biomarkers or therapeutic targets for personalized treatment strategies in this high-risk subgroup. Future research will explore how these genes contribute to PCa-specific mortality through molecular analyses, with plans to validate them in a larger validation cohort.

Keywords: 5hmC; DNA methylation; Puerto Rican Hispanic/Latino; aggressiveness; prostate cancer.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Study workflow. DEGs, Differentially expressed genes; DMGs, Differentially Methylated Genes; GE, Gene Expression; PFS, Progression free survival.
Figure 2
Figure 2
Significant DMGs associated with DNA damage and cell-cycle related pathways in PCa patients of PR H/L origin. (A) The volcano plot indicates DMGs in tumor samples (n=22) compared to adjacent normal (n=24); padj<0.05. (B) GSEA plot showing top 30 pathways significantly (padj<0.05) altered in tumor tissues compared to adjacent normal tissues. The color intensity represents level of significance.
Figure 3
Figure 3
Integration of 5hmC candidate genes from PR H/L PCa patients with UCSF 5hmC and GE dataset from PCa patients of mixed origin. (A) Van diagram showing overlapping candidate genes with UCSF 5hmC and TCGA GE datasets (padj<0.05). (B) GE (TCGA PCa dataset) and (C) 5hmC (UCSF study on PCa patients) changes in the same direction as PR H/L men.
Figure 4
Figure 4
High or low-risk PR H/L PCa patients demonstrated significantly different (P<0.05) and concordant 5hmC-GE signatures. (A) The heat map shows 111 DMGs in aggressive patients compared to indolent cases. Representative examples of genes showing association of (B) 5hmC levels (n=22) and (C) GE levels (n=86) with aggressiveness in PR H/L PCa patients. GS was used to define the risk category of each case. Low risk, GS=<6 & 3 + 4; High risk, GS=4 + 3 & >8.
Figure 5
Figure 5
5hmC and GE levels of CCDC122, NUDT15 (low), and PVT1, TRMT12, RPL30, UBR5 (high) are significantly (P<0.05) associated with poor PFS in PCa patients. Representative examples of genes showing association of (A) 5hmC levels in cfDNA (n=55) and (B) GE levels in tumor tissues (n=497) with poor PFS in PCa patients of mixed origin. The independent cohorts of PCa patients were used for this analysis. Gene expression levels were retrieved from TCGA database (n=497).
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