Assessing healthy breast tissue for evidence of ancestry-dependent molecular contributions to TNBC disparities

在一些疾病中，特定性别或祖先的人经历了更高的发病率，更具攻击性的生物学， 和不同的生存方式。在考虑了可修改的风险因素后，这些差异经常持续存在，这表明 潜在的内在原因。然而，基因组研究并没有发现DNA变化(即突变)可以 充分解释这些差异。我们的数据显示，转录组对差异有很大贡献。 领带。我们假定，研究健康组织的转录组可以揭示某些祖先的易感性。 到未来的侵略性生物学，以及在这些组织中被诊断出疾病后的差异。 该项目将利用与三类短RNA有关的研究结果：微RNA的异构体(MiRNAs) 转移RNA(TRNAs)的片段称为TRFs，核糖体的片段称为异构体 RNAs(RRNAs)称为rRFs。这些RNA的表达取决于个人属性(例如，生物属性 性别、血统)和背景(例如，组织类型、疾病类型)。此外，所有三个RNA类别都调节信使- GER RNA丰度，进而延伸到蛋白质丰度。由于它们的性质，这三个RNA类别 是研究差异的分子基础的理想工具。发表的关于多种疾病的研究结果支持 这是一道风景。与该项目相关的还有另外三个观察结果： 1.在三阴性乳腺癌(TNBC)中，来自非裔美国人(AA)患者的肿瘤显示出 基于祖先的(转录、调节)差异和更具侵略性的生物学。 2.在TNBC中，来自再障患者的肿瘤旁正常组织(NAT)样本也显示出 基于祖先的差异和更具侵略性的生物学。 3.NAT是介于健康组织和肿瘤之间的一种过渡状态，远离两端。 由于这些基于祖先的差异是在两个不同的时间点(即NAT和肿瘤)发现的，因此- 能够假设这些差异起源于更早的时间，大概是在健康的组织中。我们 假设研究健康组织中的同分异构体、TRFs和rRFs可以揭示 这些组织中的一些祖先未来具有侵略性的生物学。 我们将使用来自健康女性的真正正常的乳房样本来检验我们假设的一个具体实例。 来自三个祖先：AA，西班牙裔白人(HW)和非西班牙裔白人(NHW)。我们选择了这些祖先 因为AA和HW妇女的TNBC发病率更高，转移率更高，生存率比 不好的女人。这些标本已经可以通过印第安纳大学的Komen组织库获得。 虽然这个项目关注的是一种单一的组织类型，但我们推测，一般原则是祖先的基础-- 与异构体、TRFs和rRFs相关联的性别和年龄相关的差异。这些原则将适用于 其他组织、性别、年龄和血统组合。如果成功，该项目将产生根本性的重新 这将提供信息并指导后续对差异的重点机械性研究。

In some diseases, people of a given sex or ancestry experience a higher incidence, more aggressive biology, and different survival. The differences frequently persist after accounting for modifiable risk factors, suggesting underlying intrinsic causes. However, genomic studies did not uncover DNA changes (i.e., mutations) that can adequately explain these differences. Our data show that the transcriptome strongly contributes to dispari- ties. We posit that studying the transcriptome of healthy tissues can reveal a predisposition of some ancestries to future aggressive biology and to disparities after disease is diagnosed in these tissues. The project will leverage findings relating to three classes of short RNAs: the isoforms of microRNAs (miRNAs) known as isomiRs, the fragments of transfer RNAs (tRNAs) known as tRFs, and the fragments of ribosomal RNAs (rRNAs) known as rRFs. The expression of these RNAs depends on personal attributes (e.g., biological sex, ancestry) and context (e.g., tissue type, disease type). Additionally, all three RNA classes regulate messen- ger RNA abundance and, by extension protein abundance. Because of their properties, these three RNA classes are ideal tools for investigating the molecular basis of disparities. Published findings in multiple diseases support this view. Three additional observations are relevant for this project: 1. In triple-negative breast cancer (TNBC), tumors from African American (AA) patients show evidence of ancestry-based (transcriptomic, regulatory) differences and more aggressive biology. 2. In TNBC, normal-tissue-adjacent-to-the-tumor (NAT) specimens, too, from AA patients show evidence of ancestry-based differences and more aggressive biology. 3. NAT is an interim state between healthy tissue and tumor, and distant from both endpoints. Since these ancestry-based differences are found at two distinct time points (i.e., NAT and tumors), it is reason- able to assume that these differences have their origin further back in time, presumably in the healthy tissue. We hypothesize that studying isomiRs, tRFs, and rRFs in healthy tissues can uncover a predisposition of some ancestries to future aggressive biology in those tissues. We will test a specific instance of our hypothesis using truly normal breast specimens from healthy women from three ancestries: AA, Hispanic White (HW), and non-Hispanic white (NHW). We chose these ancestries because AA and HW women have a higher TNBC incidence, higher metastasis rates, and worse survival than NHW women. The specimens are already available through the Komen Tissue Bank at Indiana University. While this project focuses on a single tissue type, we conjecture that general principles underlie the ancestry-, sex-, and age-dependent differences that are linked to isomiRs, tRFs, and rRFs. The principles would apply to additional tissue, sex, age, and ancestry combinations. If successful, the project will generate foundational re- sults that will inform and guide subsequent focused mechanistic studies of disparities.