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

在某些疾病中，特定性别或血统的人会经历更高的发病率，更具侵略性的生物学， 不同的生存。在考虑了可改变的风险因素后，这些差异经常持续存在，这表明 潜在的内在原因。然而，基因组研究没有发现DNA变化（即，突变）， 充分解释这些差异。我们的数据显示，转录组强烈地促进了转录- 关系的我们认为，研究健康组织的转录组可以揭示某些祖先的易感性 未来的侵略性生物学和疾病在这些组织中被诊断出来后的差异。 该项目将利用与三类短RNA相关的发现：微小RNA（miRNAs） 已知为isomiR的转移RNA（tRNA）的片段，已知为tRF的转移RNA（tRNA）的片段，以及已知为tRF的核糖体RNA（RNA）的片段。 核糖核酸（rRNA），称为rRFs。这些RNA的表达取决于个人属性（例如，生物 性别、祖先）和背景（例如，组织类型、疾病类型）。此外，所有三种RNA类调节信使- 格尔RNA丰度和蛋白质丰度。由于它们的性质，这三类RNA 是研究差异的分子基础的理想工具。在多种疾病中发表的研究结果支持 这个观点。另外三项意见与本项目有关： 1.在三阴性乳腺癌（TNBC）中，来自非洲裔美国人（AA）患者的肿瘤显示出以下证据： 基于祖先的（转录组学，调节）差异和更具侵略性的生物学。 2.在TNBC中，来自AA患者的肿瘤旁正常组织（NAT）标本也显示出 基于祖先的差异和更具侵略性的生物学。 3. NAT是健康组织和肿瘤之间的过渡状态，远离两个终点。 由于这些基于祖先的差异是在两个不同的时间点发现的（即，NAT和肿瘤），这是原因- 能够假设这些差异在时间上有更早的起源，大概是在健康组织中。我们 假设研究健康组织中的isomiR、tRF和rRF可以揭示 这些组织中的一些未来侵略性生物的祖先。 我们将使用健康女性的真正正常乳房标本来测试我们假设的一个具体实例 来自三个祖先：AA、西班牙裔白色（HW）和非西班牙裔白色（NHW）。我们选择了这些祖先 因为AA和HW女性的TNBC发病率更高，转移率更高，生存率更差， NHW女性这些标本已经可以通过印第安纳州大学的科门组织库获得。 虽然这个项目集中在一个单一的组织类型，我们推测，一般原则的基础上的祖先， 与isomiR、tRF和rRF相关的性别和年龄依赖性差异。这些原则将适用于 其他组织、性别、年龄和祖先组合。如果成功，该项目将产生基础性的重新- 这些结果将为后续的差异机制研究提供信息和指导。

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.