Epigenetic variations associated with aggressiveness in prostate cancer among Puerto Rican men

摘要|完整研究项目1 波多黎各（PR）西班牙裔/拉丁裔（H/L）男性在西班牙裔中的前列腺癌（PCa）死亡率最高 人口。根据最近的PR癌症登记数据，PCa是主要的癌症类型， PR H/L男性的发病率（所有癌症病例的35%）和死亡率（所有癌症死亡的17%）。他们有 PCA特异性死亡率显著高于非西班牙裔白色（NHW）和非西班牙裔黑人（NHB）男性; 消除这一差距是我们的核心努力。虽然社会经济地位和获得医疗保健的机会 贡献者，种族群体之间分子特征的明显差异突出了肿瘤生物学的作用 在PCa中的种族差异结果。我们的长期目标是确定DNA甲基化生物标志物驱动基因 表达变化是高危人群中PCa治疗耐药性和侵袭性的基础， PR H/L的人。中心假设是肿瘤DNA甲基化模式和人群的差异 混合物与PR H/L男性PCa的药物反应和攻击性相关。基本原理是 确定PCa差异的分子基础将有助于减少致命PCa差异的负担， PR H/L的人。我们的目标将通过两个具体目标来实现：目标1）调查 PRH/L人群PCa中的侵袭性和甲基化基因以及甲基化对 他们的表情。(1a)研究与耐药性相关的差异甲基化基因， PR H/L PCa患者的侵袭性，并与来自佛罗里达PCa的NHB的甲基化数据进行比较 生物库、来自MCC和TCGA的NHW PCa患者。(1b)评估基因上的差异DNA甲基化 表达模式我们将与之前从MCC的NHW男性获得的数据进行比较， TCGA。(1c)评估群体混合是否会改变PR特异性甲基化的甲基化水平。 基因.此外，我们将研究是否基因含有祖先决定因素与 PCa的攻击性和差异性。目标二。评估DNA甲基化对PCa耐药性的贡献， 使用耐药PCa亚系的标准疗法和来自PCa患者的液体活检， 治疗(2a)利用细胞-DNA技术鉴定与耐药表型相关的差异甲基化基因 基于模型的耐药，包括去势耐药、Enzalutamide耐药和多西他赛 阻力(2b)评价耐药亚系中差异甲基化基因的表达， 敏感细胞系(2c)评估DNA甲基化抑制对耐药细胞药物敏感性的影响 表型(2d)作为一个探索性的目标，我们将评估血液中耐药相关的甲基化谱 来自既往接受过雄激素剥夺治疗、雄激素受体阻断治疗和雄激素受体阻断治疗的PR和MCC患者的样本。 靶向药物或基于紫杉烷的化疗。新的DNA甲基化的鉴定和验证 PR男性中与侵袭性和耐药PCa相关的特征有可能改善风险 分层和治疗选择在这个高风险，研究不足的人群。

ABSTRACT | FULL RESEARCH PROJECT 1 Puerto Rican (PR) Hispanic/Latino (H/L) men have the highest prostate cancer (PCa) mortality among Hispanic populations. According to the recent PR Cancer Registry data, PCa is the leading cancer type in terms of incidence (35% of all cancer cases) and mortality (17% of all cancer deaths) in PR H/L men. They have significantly higher PCa-specific mortality than non-Hispanic white (NHW) and non-Hispanic Black (NHB) men; addressing this gap constitutes our central efforts. While socioeconomic status and access to healthcare are contributors, manifest differences in molecular features between racial groups highlight the role of tumor biology in racially disparate outcomes in PCa. Our long-term goal is to identify DNA methylation biomarkers driving gene expression changes that underly PCa therapy resistance and aggressiveness in at-risk populations, particularly PR H/L men. The central hypothesis is that differences in tumor DNA methylation patterns and population admixture are associated with drug response and aggressiveness in PCa in PR H/L men. The rationale is that identifying the molecular basis of PCa disparities will serve to reduce the burden of lethal PCa disparities affecting PR H/L men. Our goals will be accomplished through two Specific Aims: Aim 1) Investigate associations between aggressiveness and methylated genes in PCa among the PR H/L population and the impact of methylation on their expression. (1a) Investigate differentially methylated genes associated with drug resistance and aggressiveness among PR H/L PCa patients and compare with methylation data from NHB from the Florida PCa biobank, NHW PCa patients from MCC, and TCGA. (1b) Evaluate differential DNA methylation on gene expression patterns. We will establish comparisons with previous data obtained from NHW men from MCC and TCGA. (1c) Evaluate whether population admixture will modify the methylation level of PR-specific methylated genes. Further, we will investigate whether genes that contain ancestry determinants are associated with the aggressiveness of PCa and disparity. Aim 2. Assess the contribution of DNA methylation to PCa resistance to standard therapies using drug-resistant PCa sublines and liquid biopsies from PCa patients progressing after treatment. (2a) Identify differentially methylated genes associated with drug-resistant phenotypes using cell- based models of drug resistance including castration resistance, enzalutamide resistance, and docetaxel resistance. (2b) Evaluate the expression of differentially methylated genes in resistant sublines compared to sensitive cell lines. (2c) Assess the effect of DNA methylation inhibition on drug sensitivity in resistant phenotypes. (2d) As an exploratory aim, we will evaluate resistance-associated methylation profiles in blood samples from PR and MCC patients previously treated with androgen deprivation therapy, androgen receptor- targeting agents, or taxane-based chemotherapy. The identification and validation of novel DNA methylation signatures associated with aggressive and drug-resistant PCa in PR men have the potential to improve risk stratification and treatment selection in this high-risk, understudied population.