LBPO.PS01 · 人群科学 · Late-Breaking

历史性红线划分与前列腺肿瘤中的DNA甲基化

Historical redlining and DNA methylation in prostate tumors

编号 LB376 展板 6 时间 4/21 02:00–05:00 区域 Section 55 主讲 Joseph Boyle, PhD

分会场 Late-Breaking Research: Population Sciences

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作者与单位 Authors & Affiliations

Joseph Boyle¹, Camryn Cohen², Derrick Butts³, Jimmie L. Slade⁴, Yuji Zhang², Teklu B. Legesse⁵, Ashley Johnson⁶, Kimberly Clark⁶, Jessica Wimbush⁷, Nicholas Ambulos⁸, Jing Yin⁸, Jong Y. Park⁹, Eberechukwu Onukwugha¹⁰, Arif Hussain¹¹, Cheryl L. Knott¹², Kathryn H. Barry²

¹Department of Family Medicine and Population Health, School of Medicine, Virginia Commonwealth University, Richmond, VA,²Department of Epidemiology and Public Health, School of Medicine, University of Maryland, Baltimore, MD,³Prostate Health Matters, Washington, DC,⁴Maryland Community Health Engagement Partnership, Upper Marlboro, MD,⁵Department of Pathology, School of Medicine, University of Maryland, Baltimore, MD,⁶Pathology Biorepository Shared Resource, Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD,⁷Tumor Registry, Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD,⁸Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, MD,⁹H. Lee Moffitt Cancer Center, Tampa, FL,¹⁰Department of Practice, Sciences, and Health Outcomes Research, School of Pharmacy, University of Maryland, Baltimore, MD,¹¹Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD,¹²Department of Behavioral and Community Health, University of Maryland, College Park, College Park, MD

摘要 Abstract

中文摘要

引言。越来越多的文献表明，社区劣势（ND）在按种族划分的前列腺癌（PC）差异中发挥作用，而ND对非裔美国（AA）男性的影响尤为不成比例。ND的一个组成部分是历史性红线划分，其涉及在某些城市社区系统性地拒绝提供抵押贷款，通常基于种族。红线划分导致了投资撤离并随时间推移形成ND，并已与当今较差的健康结局相关联。与慢性应激相关的表观遗传扰动可能在这些关联中发挥作用。我们假设居住于曾被红线划分的社区将与前列腺肿瘤DNA甲基化（DNAm）改变相关。方法。这项横断面研究利用了1992-2021年间在马里兰大学医学中心接受根治性前列腺切除术的AA前列腺癌男性的前列腺肿瘤DNAm数据。历史性红线划分状态通过将参与者诊断时的地址与巴尔的摩都市区20世纪30年代房主贷款公司红线划分地图相交叠来确定。DNAm采用Illumina的EPIC v2芯片测量。经质量控制步骤后，共有683,765个CpG位点用于分析。采用线性回归模型估计历史性红线划分与DNAm水平（β值，范围0-1）之间的关联，并调整手术时年龄和手术年份。使用bumphunter R软件包识别差异甲基化区域（DMR）。结果。我们纳入了92名AA男性，手术时中位（四分位距，IQR）年龄为60（54-63）岁。8名男性（9%）居住于历史性红线划分社区。经多重比较校正后[错误发现率（FDR）校正p<0.05]，居住于红线划分社区与12个CpG位点的DNAm显著相关，其中10个表现为低甲基化[差异的IQR：(-0.14, -0.07)]。这些位点注释到九个基因：PLEKHG5、KDR、ZDHHC19、ZNF316、ZFYVE21、CDH26、HPCA、FAM228B、PTPRN2。最显著的CpG位点（cg11384525）位于ZDHHC19，该基因通过S-棕榈酰化活性在肿瘤进展中发挥作用（红线划分社区 vs. 非红线划分社区男性的平均DNAm：0.76 vs. 0.92；p=6.4×10⁻⁹；FDR校正p=2.2×10⁻³）。我们识别出一个涉及TNXB低甲基化的显著DMR，TNXB编码一种细胞外基质糖蛋白，与包括PC在内的多种癌症的肿瘤进展相关。讨论。在这项针对AA前列腺癌男性的研究中，居住于历史性红线划分社区的男性在12个CpG位点的肿瘤DNAm水平存在显著差异。本研究是首批提示历史性红线划分与前列腺肿瘤DNAm相关的研究之一。需要进一步研究以重复这些发现，并深入探究社区环境、表观遗传肿瘤修饰与PC差异之间的关系，以阐明机制并为干预提供依据。

查看英文原文 English abstract

Introduction. Growing literature demonstrates a role of neighborhood disadvantage (ND), which disproportionately affects African American (AA) men, in prostate cancer (PC) disparities by race. One component of ND is historical redlining, which involved the systematic denial of mortgages in certain urban neighborhoods, often based on race. Redlining led to disinvestment and subsequent ND over time, and has been linked with poorer health outcomes in the present day. Epigenetic perturbations related to chronic stress may play a role in these associations. We hypothesized that residing in a formerly redlined neighborhood would be associated with prostate tumor DNA methylation (DNAm) alterations. Methods. This cross-sectional study leveraged prostate tumor DNAm data for AA men with PC who received radical prostatectomy at the University of Maryland Medical Center between 1992-2021. Historical redlining status was determined by intersecting participants' address at diagnosis with the 1930s Home Owners' Loan Corporation redlining map of the Baltimore metropolitan area. DNAm was measured using Illumina's EPIC v2 array. After quality control steps, there were 683,765 CpG sites for analysis. Linear regression models were used to estimate associations between historical redlining and DNAm levels (beta values, ranging from 0-1), adjusting for age at surgery and year of surgery. Differentially methylated regions (DMRs) were identified using the bumphunter R package. Results. We included 92 AA men with a median (interquartile range, IQR) age of 60 (54-63) years at surgery. Eight men (9%) lived in a historically redlined neighborhood. Residence in a redlined neighborhood was significantly associated with DNAm at 12 CpG sites after adjustment for multiple comparisons [False Discovery Rate (FDR)-adjusted p<0.05], 10 of which exhibited hypomethylation [IQR for difference: (-0.14, -0.07)]. These sites annotated to nine genes: PLEKHG5, KDR, ZDHHC19, ZNF316, ZFYVE21, CDH26, HPCA, FAM228B, PTPRN2 . The most significant CpG site (cg11384525) was in ZDHHC19 , which plays a role in tumor progression via S-palmitoylation activity (mean DNAm for men in redlined vs. non-redlined neighborhoods: 0.76 vs. 0.92; p=6.4x10 -9 ; FDR-adjusted p=2.2x10 -3 ). We identified one significant DMR involving hypomethylation of TNXB , which encodes an extracellular matrix glycoprotein that is associated with tumor progression for several cancers, including PC. Discussion. In this study of AA men with PC, tumor DNAm levels at 12 CpG sites were significantly different among men who resided in historically redlined neighborhoods. This study is one of the first to suggest associations of historical redlining with prostate tumor DNAm. Additional research is needed to replicate these findings and further investigate the relationships between the neighborhood environment, epigenetic tumor modifications, and PC disparities to elucidate mechanisms and inform interventions.

利益披露 Disclosure

J. Boyle, None.. C. Cohen, None.. D. Butts, None.. J. L. Slade, None.. Y. Zhang, None.. T. B. Legesse, None.. A. Johnson, None.. K. Clark, None.. J. Wimbush, None.. N. Ambulos, None.. J. Yin, None.. J. Y. Park, None.. E. Onukwugha, None. A. Hussain, Constellation Pharmaceuticals, Inc. ). FORMA Therapeutics ). AstraZeneca ). PSI Pharma Support America, Inc. ). Taiho Oncology, Inc ). Orion Corporation ). Regeneron Pharmaceuticals, Inc ). Pfizer, Inc ). Poseida Therapeutics, Inc ). Exelixis, Inc ). Aravive, Inc ). Bayer Corporation ). Future Chem Co Ltd ). Merck Sharp & Dohme LLC ). Nimbus Saturn ). ORIC Pharmaceuticals, Inc ). Advancing Cancer Treatment ). C. L. Knott, None.. K. H. Barry, None.

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