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

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， 只有少数关于种族相关的可操作突变和聚合基因差异的研究 表情。因此，这些努力很可能错过了与种族相关的NSCLC生物学的其他重要驱动因素 和临床异质性。拟议的工作解决了迫切需要从功能上刻画和 在非小细胞肺癌中调节新的种族相关RNA剪接靶点以用于潜在的治疗应用。 我们是第一个发现非小细胞肺癌患者之间存在选择性RNA剪接差异的团队 非洲和欧洲血统。具体地说，在肺鳞状细胞癌(LUSCs)中，RACE-1的数量- 相关差异剪接基因(DGs)(4,830个)远远超过显示种族相关基因的数量 在相同组织中差异聚合基因表达(Degs)(267)。在DSG中，报告的比例为17% DSG中的癌基因、肿瘤抑制基因和/或驱动因素以及355个RNA剪接事件是 与LUSC的生存有关。据报道，在这些患者中，6%与癌症有关，18%与癌症有关。 与LUSC的生存有关。许多DSG和DEG涉及治疗靶向的信号通路。 此外，我们还挖掘了癌症基因组图谱(TCGA)，并在 其他LUSC或肺腺癌(LUADs)。 拟议工作的目的是扩展这一新的调查领域，并对精确度具有重要意义 非小细胞肺癌的肿瘤学研究：1)评估RNA剪接变异体和编码反式作用的基因的表达 非洲和欧洲血统患者临床相关非小细胞肺癌亚群的剪接因子，2) 询问优先的种族相关RNA剪接变异体对非小细胞肺癌生物学的功能意义， 和3)开发新型剪接开关寡核苷酸(SSO)吗啡诺药物来调节RNA剪接 对种族相关的非小细胞肺癌的潜在治疗应用至关重要的事件。 这项研究的理论基础和影响是它将1)增加对分子的理解 肺癌差异的机制，2)提供了大量与RNA剪接相关的新靶点 为非洲血统的非小细胞肺癌患者开发新的生物标记物和治疗剂，3) 结合TCGA数据，这项研究将使分子特征的非小细胞肺癌的数量增加一倍以上 来自非洲血统患者的生物标本，使这样的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 非洲血统非小细胞肺癌患者体内研究的药物。最终，如此精确的肿瘤学 干预措施和进一步的研究将由分子特征的生物旋毛虫队列实现 减少非小细胞肺癌差距的潜力。

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.