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

评估健康乳腺组织，寻找祖先依赖性分子对 TNBC 差异贡献的证据

• 批准号: 10649103
• 负责人: Isidore Rigoutsos
• 金额: $ 41.38万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649103
• 关键词: Accounting; African American; Age; Back; Biological Factors; Biology; Black race; Breast; Cancer Biology; Cells; DNA; Data; Diagnosis; Diagnostic; Disease; Disparity; Distant; Environmental Risk Factor; Event; Exhibits; Future; Genetic; Genetic Transcription; Genetic study; Genomics; Health; Hispanic; Human; Human Biology; Incidence; Indiana; Individual; Letters; Link; Malignant Neoplasms; Mammary Gland Parenchyma; Messenger RNA; MicroRNAs; Molecular; Molecular Biology; Mutation; Neoplasm Metastasis; Normal tissue morphology; Not Hispanic or Latino; Outcome; Pathway interactions; Patients; Personal Attribute; Persons; Predisposition; Property; Protein Isoforms; Proteins; Publishing; RNA; Resistance; Resources; Ribosomal RNA; Risk Factors; Specimen; Testing; The Cancer Genome Atlas; Time; Tissue Banks; Tissues; Transcript; Transfer RNA; Tumor Biology; Universities; Untranslated RNA; Woman; Work; age related; aggressive breast cancer; base; biobank; biological sex; cancer health disparity; cell behavior; experience; health disparity; healthy volunteer; improved; malignant breast neoplasm; modifiable risk; prognostic; sex; socioeconomics; tool; transcriptome; transcriptomics; triple-negative invasive breast carcinoma; tumor

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.

在某些疾病中，有性别或祖先的人会经历更高的发病率，更具侵略性的生物学， 和不同的生存。考虑到可修改的风险因素后，差异经常持续存在，表明 根本的固有原因。但是，基因组研究并未发现可以发现的DNA变化（即突变） 充分解释这些差异。我们的数据表明，转录组强烈有助于不同 关系。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 在这些组织中诊断出未来的攻击性生物学和疾病后的差异。 该项目将利用与三类简短RNA相关的发现：microRNA的同工型（miRNA） 称为Isomirs，被称为TRF的转移RNA（TRNA）的片段和核糖体的片段 RNA（RRNA）称为RRFS。这些RNA的表达取决于个人属性（例如，生物学 性别，祖先）和背景（例如，组织类型，疾病类型）。此外，所有三个RNA类都调节Messen- GER RNA丰度，并通过扩展蛋白质丰度。由于其特性，这三个RNA类 是研究差异分子基础的理想工具。多种疾病支持中发表的发现 这个观点。与该项目有关的另外三个观察结果： 1。在三阴性乳腺癌（TNBC）中，来自非裔美国人（AA）患者的肿瘤显示了证据 基于祖先的（转录组，调节）差异和更具侵略性的生物学。 2。在TNBC中，AA患者的正常组织 - 肿瘤对肿瘤（NAT）标本也显示出证据表明 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临时状态，远离两个终点。 由于这些基于祖先的差异在两个不同的时间点（即NAT和肿瘤）发现，因此是理性的 能够假设这些差异的起源是及时的，大概是在健康组织中。我们 假设健康组织中研究异构体，TRF和RRF可以发现 一些组织中未来侵略性生物学的一些祖先。 我们将使用健康女性的真正正常乳房标本来检验假设的特定实例 来自三个祖先：AA，西班牙裔白（HW）和非西班牙裔白色（NHW）。我们选择了这些祖先 因为AA和HW妇女的发病率更高，转移率更高，生存率较差 NHW妇女。这些标本已经可以通过印第安纳大学的Komen Tissue Bank获得。 尽管该项目着重于一种单一的组织类型，但我们认为，一般原则是祖先 - 与Isomirs，TRF和RRF相关的性别和年龄依赖性差异。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 将为和指导随后的重点机理研究提供信息和指导差异的诉讼。