Race-related differential RNA splicing: novel targets for precision oncology in non-small cell lung cancer

种族相关的差异RNA剪接：非小细胞肺癌精准肿瘤学的新靶点

• 批准号: 10056237
• 负责人: Jeffrey Melson Clarke
• 金额: $ 37.71万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-24 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056237
• 关键词: Address; African; African American; Age; Alternative Splicing; Area; Biological; Biological Markers; Biological Specimen Banks; Biology; Bronchi; CRISPR/Cas technology; Cancer Center; Cancer Etiology; Cancer Patient; Cancer cell line; Cells; Cellular biology; Cessation of life; Characteristics; Clinical; Data; Development; Diagnosis; Drug Targeting; Ethnic Origin; European; Event; Exhibits; Gene Expression; Genes; Genetic Transcription; Genotype; Intervention; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Methodology; Modeling; Molecular; Non-Small-Cell Lung Carcinoma; Oligonucleotides; Oncogenic; Pathology; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Positioning Attribute; RNA Splicing; Race; Reagent; Reporting; Research; Scientist; Signal Pathway; Smoking Status; Spliced Genes; Squamous Cell Lung Carcinoma; Subgroup; Technology; The Cancer Genome Atlas; Therapeutic; Therapeutic Agents; Tissues; Transfection; Tumor Suppressor Genes; United States; Variant; Work; actionable mutation; base; biobank; biological heterogeneity; cancer care; cancer health disparity; clinical heterogeneity; clinically relevant; cohort; driver mutation; exon skipping; improved; in vivo; interest; novel; patient subsets; precision oncology; therapeutic target; tool; transcriptome; transcriptome sequencing

Biological drivers of non-small cell lung cancer (NSCLC) in black patients remain underexplored, with only a small number of studies on race-related differences in actionable mutations and aggregate gene expression. As a result, these efforts have likely missed other important drivers of race-related NSCLC biological and clinical heterogeneity. The proposed work addresses the urgent need to functionally characterize and modulate novel race-related RNA splicing targets in NSCLC for potential therapeutic application. We are the first team to identify alternative RNA splicing differences in NSCLC between patients of African and European ancestry. Specifically, in lung squamous cell carcinomas (LUSCs), the number of race- related differentially spliced genes (DSGs) (4,830) far exceeded the number of genes exhibiting race-related differential aggregate gene expression (DEGs) (267) in the same tissues. Among the DSGs, 17% are reported to be oncogenes, tumor suppressor genes and/or drivers and 355 RNA splicing events within DSGs are associated with LUSC survival. Among the DEGs, 6% are reported to be cancer-related and 18 are associated with LUSC survival. A number of the DSGs and DEGs involve therapeutically targetable signaling pathways. Furthermore, we have mined The Cancer Genome Atlas (TCGA) and have identified DSGs and DEGs in additional LUSCs or lung adenocarcinomas (LUADs). The aims of the proposed work are to extend this novel area of inquiry with significance for precision oncology in NSCLC by 1) assessing the expression of RNA splice variants and genes encoding trans-acting splicing factors across clinically relevant NSCLC subgroups in patients of African and European ancestry, 2) interrogating the functional significance of prioritized race-related RNA splice variants for the biology of NSCLC, and 3) developing novel splice-switching oligonucleotide (SSO) morpholino drugs to modulate RNA splicing events critical to race-related NSCLC for potential therapeutic application. The rationale for and impact of this study is that it will 1) increase understanding of the molecular mechanisms underlying lung cancer disparities, 2) provide an abundance of novel RNA splicing-related targets for development of new biomarkers and therapeutic agents for NSCLC in patients of African ancestry, 3) when combined with TCGA data, this study will more than double the number of molecularly characterized NSCLC biospecimens from patients of African ancestry, making such data available to the nationwide cohort of scientists conducting research on lung cancer and lung cancer disparities, and 4) position novel RNA splicing-targeted drugs for NSCLC in patients of African ancestry for in vivo studies. Ultimately, such precision oncology interventions and further studies enabled by the molecularly characterized cohort of biospecimens will have the potential to mitigate NSCLC disparities.

黑人患者非小细胞肺癌（NSCLC）的生物驱动因素仍未得到充分研究， 只有少数研究种族相关的差异，在可操作的突变和聚合基因， 表情因此，这些努力可能错过了种族相关NSCLC生物学的其他重要驱动因素， 和临床异质性。拟议的工作涉及迫切需要在功能上确定 调节NSCLC中新的种族相关RNA剪接靶点，用于潜在的治疗应用。 我们是第一个确定非小细胞肺癌患者之间选择性RNA剪接差异的团队， 非洲和欧洲血统。具体而言，在肺鳞状细胞癌（LUSC）中， 相关的差异剪接基因（DSG）（4，830）远远超过表现出种族相关的基因数量。 差异聚集基因表达（DEG）（267）在相同的组织。在DSG中，报告了17% 是癌基因、肿瘤抑制基因和/或驱动基因，DSG内的355个RNA剪接事件是 与LUSC存活率相关。在DEG中，6%报告与癌症相关，18例与癌症相关。 LUSC生存许多DSG和DEG涉及治疗靶向信号传导途径。 此外，我们已经挖掘了癌症基因组图谱（TCGA），并确定了DSG和DEG， 另外的LUSC或肺腺癌（LUAD）。 拟议的工作的目的是扩大这一新的调查领域与意义的精度 通过1）评估RNA剪接变体和编码反式作用的基因的表达， 非洲和欧洲血统患者中临床相关NSCLC亚组的剪接因子，2） 询问优先考虑的种族相关RNA剪接变体对NSCLC生物学的功能意义， 以及3）开发新型剪接转换寡核苷酸（SSO）吗啉代药物以调节RNA剪接 对人种相关NSCLC的潜在治疗应用至关重要的事件。 这项研究的基本原理和影响是：1）增加对分子生物学的理解， 肺癌差异的潜在机制，2）提供了大量新的RNA剪接相关靶点 为非洲血统患者开发新的NSCLC生物标志物和治疗药物，3）当 结合TCGA数据，这项研究将使分子特征的NSCLC数量增加一倍以上， 来自非洲血统患者的生物标本，使这些数据可供全国科学家队列使用 进行肺癌和肺癌差异的研究，以及4）定位新的RNA剪接靶向 用于体内研究的非裔NSCLC患者的药物。最终，这种精确的肿瘤学 通过生物样本的分子特征队列实现的干预和进一步研究将具有 缓解NSCLC差异的潜力。