PO.PR01.01 · 预防研究
非裔美国人相比欧裔美国人前列腺癌患者中基质ERV甲基化升高：在19号染色体上的富集
Increased stromal ERV methylation in African American compared to European American prostate cancer patients: Enrichment on chromosome 19
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：非裔美国（AA）男性的前列腺癌（PCa）预后比欧裔美国（EA）男性更差，包括更高的PSA水平、更大的肿瘤、更早的发病以及更具侵袭性的疾病进展。这些差异即使在考虑了医疗可及性和社会经济因素后仍然存在，提示存在潜在的生物学因素。内源性逆转录病毒（ERVs）通常通过DNA甲基化被沉默，现已成为抗肿瘤免疫活性的调节因子以及PCa中有效的预后标志物。尽管ERVs占人类基因组的8%，其在肿瘤微环境中的作用仍未被完全理解。在我们此前的研究中，与EA患者相比，与抗肿瘤免疫活性相关的通路在AA PCa患者的肿瘤邻近基质（TAS）中被显著更高程度地甲基化和沉默，提示可能存在促成所观察到差异的表观遗传学差异。
方法：我们对来自17例AA和15例EA PCa患者的TAS组织进行了甲基结合域测序（MBD-seq）和RNA测序（RNA-seq）。开发了两条定制生物信息学流程：一条用于ERV甲基化分析，另一条用于ERV表达分析。对于甲基化，将测序读段比对到从人类内源性逆转录病毒数据库（HERVd）整理的ERVs，以量化位点特异性甲基化。对于表达，将RNA-seq数据比对到同一数据库以评估ERV表达谱。使用chromoMap可视化ERV甲基化模式及其染色体分布。
结果：在肿瘤邻近基质中，非裔美国患者表现出显著更高的整体ERV甲基化伴较低表达，而欧裔美国患者表现出甲基化降低伴转录活性升高（p < 0.05）。ChromoMap和统计分析显示甲基化ERVs的染色体分布为非随机，最显著的与祖源相关的差异位于19号染色体（AA：2.09 vs. EA：1.76，p < 10⁻¹⁵⁹），该染色体具有最高的甲基化水平，与其富集重复元件和ERV序列相一致。Y染色体未显示显著差异（p = 0.148），可能是由于跨祖源间的组成型异染色质状态。
结论：在TAS中，AA患者通过高甲基化增强的ERV沉默可能代表一种潜在的表观遗传机制，通过改变免疫应答基因促成疾病侵袭性。反之，EA患者中低甲基化且具转录活性的ERVs可能增强抗肿瘤免疫信号，从而可能解释不同人群间不同的临床结局。
查看英文原文 English abstract
Background : African American (AA) men experience worse prostate cancer (PCa) outcomes than European American (EA) men, including higher PSA levels, larger tumors, earlier onset, and more aggressive disease progression. These disparities persist even after accounting for healthcare access and socioeconomic factors, suggesting underlying biological contributors. Endogenous retroviruses (ERVs), normally silenced through DNA methylation, have emerged as regulators of anti-tumor immune activity and as effective prognostic markers in PCa. Despite constituting 8% of the human, ERVs' role in the tumor microenvironment remains incompletely understood. In our previous study, pathways associated with anti-tumor immune activity were significantly more methylated and silenced in AA PCa patients in the tumor-adjacent stroma (TAS) compared to EA patients, indicating potential epigenetic differences that may contribute to observed disparities.
Methods : We performed methyl-binding domain sequencing (MBD-seq) and RNA sequencing (RNA-seq) on TAS tissue from 17 AA and 15 EA PCa patients. Two custom bioinformatic pipelines were developed: one for ERV methylation analysis and another for ERV expression analysis. For methylation, sequencing reads were mapped to ERVs curated from the Human Endogenous Retrovirus Database (HERVd) to quantify locus-specific methylation. For expression, RNA-seq data were aligned to the same database to assess ERV expression profiles. ERV methylation patterns and their chromosomal distribution were visualized using chromoMap.
Results: In tumor-adjacent stroma, African American patients demonstrated significantly higher global ERV methylation with lower expression, while European American patients exhibited reduced methylation with elevated transcriptional activity (p<0.05). ChromoMap and statistical analysis revealed non-random chromosomal distribution of methylated ERVs, with the most significant ancestry-related differences on chromosome 19 (AA: 2.09 vs. EA: 1.76, p<10⁻¹⁵⁹), which harbored the highest methylation levels, consistent with its enrichment for repetitive elements and ERV sequences. Chromosome Y showed no significant difference (p=0.148), potentially due to constitutive heterochromatin status across ancestries.
Conclusion : In TAS, enhanced ERV silencing through hypermethylation in AA patients may represent a potential epigenetic mechanism contributing to disease aggressiveness through altered immune response genes. Conversely, hypomethylated and transcriptionally active ERVs in EA patients may enhance antitumor immune signaling, potentially explaining distinct clinical outcomes between populations.
利益披露 Disclosure
T. S. K. Jennings, None..
L. Ueta, None..
V. Kumar, None..
A. Afsari, None..
E. Arbzadeh, None..
P. Castro, None..
M. M. Ittmann, None..
Y. Zhao, None..
M. Daneshvar, None..
F. Rahmatpanah, None.