Long noncoding RNA regulations in breast cancer among African-American women

非洲裔美国女性乳腺癌中的长非编码 RNA 调控

• 批准号: 10053610
• 负责人: Zhihong Gong
• 金额: $ 39.22万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10053610
• 关键词: Aberrant DNA Methylation; African American; American; Biological; Biological Assay; Breast Cancer Patient; Cancer Prognosis; Cells; Characteristics; Clinical; Code; DNA Methylation; Data; Development; Diagnosis; Diet; Disease; Economic Factors; Environmental Exposure; Estrogen Receptor Status; Estrogen Receptors; European; Exhibits; Expression Profiling; Genes; Genetic Transcription; HAS2 gene; Health; In Vitro; Knowledge; Life Style; Machine Learning; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Methylation; MicroRNAs; Molecular; Mutation; Normal tissue morphology; Obesity; Outcome; Pathologic; Patients; Pattern; Pilot Projects; Play; Prevention strategy; Prognostic Marker; Promoter Regions; Proteins; Race; Regulation; Research; Role; Specificity; Therapeutic; Tissue Banks; Tissues; Translating; Tumor Biology; Tumor Tissue; Untranslated RNA; Validation; Woman; Work; base; breast cancer survival; cancer health disparity; carcinogenesis; cohort; cost effective; diagnostic biomarker; differential expression; epidemiologic data; experience; gene function; genome-wide; genome-wide analysis; health care availability; high risk; lifestyle factors; malignant breast neoplasm; mortality; next generation sequencing; novel; outcome forecast; overexpression; public health relevance; racial difference; racial disparity; socioeconomics; targeted treatment; therapeutic target; transcriptome; transcriptome sequencing; tumor; tumor growth; tumor progression

ABSTRACT Breast cancer rates among African-American (AA) women continue to rise and may further widen breast cancer disparities experienced by AA women, who are more likely to develop aggressive tumor types with a worse prognosis. The biological reasons for these differences remain largely unknown. Recent genome-wide, high-throughput studies highlight an emerging role of long noncoding RNAs (lncRNAs) as a novel class of regulatory molecules in cancer. LncRNAs form an important regulatory layer in global gene expression, and increasing evidence indicates that abnormal expression of specific lncRNAs can contribute to breast cancer carcinogenesis and progression. Studies to date, however, are focused exclusively on EA women, have not commonly used high-throughput next generation sequencing (NGS) to provide unbiased comprehensive profiling, and mostly do not incorporate rigorous normal tissue controls. Motivated by these research gaps and limitations, we recently completed a pilot study of genome-wide lncRNA expression profiling in normal and tumor breast tissues from AA and EA women. LncRNA expression data showed clear tissue- and subtype- specific expression patterns. Importantly, we noted a number of differentially abundant lncRNAs between AA and EA women by estrogen receptor (ER) status. These results indicate that there are unique lncRNA expression patterns in AA tumors, which we hypothesize contributes to aggressive tumor biology and high breast cancer-related mortality. We propose a cost-effective study in a well-characterized cohort of AA breast cancer patients in the Women’s Circle of Health Study (WCHS), which has available tumor tissue blocks, and extensive data on tumor characteristics, clinical outcomes, treatments received, lifestyle factors, and genome- wide DNA methylation. As such, our Specific Aims are: 1) Perform tissue lncRNA expression profiling using total RNA sequencing (1181 AA cases from WCHS and 100 AA controls from Komen Tissue Bank) to determine lncRNAs that are breast cancer- and ER subtype- specific (tumor, ER+, ER- vs. normal) and those associated with clinico-pathological factors (e.g., grade); 2) Examine associations of lncRNA expression levels with breast cancer survival, and use a machine learning approach to identify a combined panel of lncRNAs associated with breast cancer survival; and further perform computational prediction and in vitro functional assays to determine their biological relevance; and 3) Integrate paired data on lncRNA expression and DNA methylation to determine which of these cancer- and prognosis-relevant lncRNAs are regulated by DNA methylation, and explore whether diet, obesity and other lifestyle-related factors are associated with aberrant DNA methylation. This work is novel and findings are anticipated to advance our understanding of molecular mechanisms contributing to aggressive tumor biology and poor cancer prognosis observed in AA women that can be translated into the development of targeted strategies for prevention and therapeutics.

抽象的 非裔美国 (AA) 女性乳腺癌发病率持续上升，乳房可能进一步扩大 AA 女性经历的癌症差异，她们更有可能患上侵袭性肿瘤类型 预后较差。这些差异的生物学原因仍然很大程度上未知。最近全基因组， 高通量研究强调了长非编码 RNA (lncRNA) 作为一类新型RNA的新兴作用 癌症中的调节分子。 LncRNA 形成全局基因表达的重要调控层，并且 越来越多的证据表明特定 lncRNA 的异常表达可能导致乳腺癌 癌发生和进展。然而，迄今为止的研究仅针对 EA 女性，尚未发现 常用的高通量下一代测序（NGS）提供无偏见的综合 分析，并且大多不包含严格的正常组织控制。受到这些研究空白的激励 由于局限性，我们最近完成了一项针对正常和正常人群中全基因组 lncRNA 表达谱的初步研究。 AA 和 EA 女性的肿瘤乳腺组织。 LncRNA 表达数据显示清晰的组织和亚型 具体的表达模式。重要的是，我们注意到 AA 之间存在许多差异丰度的 lncRNA 和 EA 女性的雌激素受体 (ER) 状态。这些结果表明存在独特的lncRNA AA 肿瘤中的表达模式，我们假设这有助于侵袭性肿瘤生物学和高 乳腺癌相关死亡率。我们建议在一个特征明确的 AA 乳房队列中进行一项具有成本效益的研究 女性健康圈研究 (WCHS) 中的癌症患者，该研究有可用的肿瘤组织块，以及 关于肿瘤特征、临床结果、接受的治疗、生活方式因素和基因组的广泛数据 广泛的DNA甲基化。因此，我们的具体目标是：1) 使用以下方法进行组织 lncRNA 表达谱分析： 总 RNA 测序（来自 WCHS 的 1181 例 AA 病例和来自 Komen 组织库的 100 例 AA 对照） 确定乳腺癌和 ER 亚型特异性的 lncRNA（肿瘤、ER+、ER- 与正常）以及那些 与临床病理因素（例如分级）相关； 2) 检查lncRNA表达水平的关联 与乳腺癌存活率相关，并使用机器学习方法来识别一组 lncRNA 的组合 与乳腺癌生存相关；并进一步进行计算预测和体外功能 测定其生物学相关性； 3) 整合 lncRNA 表达和 DNA 的配对数据 甲基化以确定哪些与癌症和预后相关的 lncRNA 受 DNA 调节 甲基化，并探讨饮食、肥胖和其他生活方式相关因素是否与异常相关 DNA甲基化。这项工作是新颖的，预计发现将增进我们对分子的理解 在 AA 女性中观察到的导致侵袭性肿瘤生物学和不良癌症预后的机制 可以转化为制定有针对性的预防和治疗策略。