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

摘要 非裔美国人(AA)女性的乳腺癌发病率继续上升，并可能进一步扩大乳房 AA女性的癌症差异，她们更有可能患上侵袭性肿瘤类型 预后更差。造成这些差异的生物学原因在很大程度上仍不清楚。最新的全基因组， 高通量研究强调了长非编码RNA(LncRNAs)作为一类新的 癌症中的调节分子。LncRNAs在全球基因表达中形成一个重要的调节层，并且 越来越多的证据表明，特定的lncRNAs的异常表达可能导致乳腺癌 癌症的发生和发展。然而，到目前为止，研究仅仅集中在EA女性身上，还没有 常用的高通量下一代测序(NGS)，以提供无偏见的全面 侧写，而且大多不包括严格的正常组织控制。受这些研究差距和 限制，我们最近完成了一项全基因组lncRNA表达谱的初步研究，正常和 AA和EA妇女的乳腺肿瘤组织。LncRNA表达数据显示明显的组织和亚型- 特定的表达模式。重要的是，我们注意到aa之间存在大量差异丰富的lncRNA。 和雌激素受体(ER)状态的电针女性。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水平 乳腺癌相关死亡率。我们建议在一组特征良好的AA乳房队列中进行一项成本效益研究。 女性健康圈癌症患者研究(WCHS)，其中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 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)至 确定乳腺癌和ER亚型特异的lncRNA(肿瘤、ER+、ER-vs.正常)以及 与临床病理因素(例如，级别)相关；2)检查lncRNA表达水平的相关性 并使用机器学习方法来识别一组组合的lncRNA 与乳腺癌的存活率相关；并进一步进行计算预测和体外功能 检测以确定它们的生物学相关性；以及3)整合关于lncRNA表达和DNA的配对数据 甲基化以确定这些与癌症和预后相关的lncRNAs中哪些受DNA调控 甲基化，并探索饮食、肥胖和其他与生活方式相关的因素是否与异常相关 DNA甲基化。这项工作是新颖的，这些发现有望促进我们对分子的理解 在再生障碍性贫血妇女中观察到导致侵袭性肿瘤生物学和不良癌症预后的机制 可转化为制定有针对性的预防和治疗战略。

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.