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

基本信息

  • 批准号:
    10649103
  • 负责人:
  • 金额:
    $ 41.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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,特定性别或祖先的人发病率更高,更具侵略性,

项目成果

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Isidore Rigoutsos其他文献

Isidore Rigoutsos的其他文献

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{{ truncateString('Isidore Rigoutsos', 18)}}的其他基金

Specialized Tools and Auto-updatable Scalable Interactive Databases to Study isomiRs, tRFs and rRFs in Human and Mouse
用于研究人类和小鼠 isomiR、tRF 和 rRF 的专用工具和可自动更新、可扩展的交互式数据库
  • 批准号:
    10736401
  • 财政年份:
    2023
  • 资助金额:
    $ 41.38万
  • 项目类别:
Discovery of Novel miRNAs and isomiRs and Use in Sub-typing TCGA Cancers
新型 miRNA 和 isomiR 的发现及其在 TCGA 癌症分型中的应用
  • 批准号:
    9188070
  • 财政年份:
    2015
  • 资助金额:
    $ 41.38万
  • 项目类别:

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