Characterizing genome-wide alternative splicing in HPV related HNSCC

 描述(申请人提供)：与头颈部鳞状细胞癌(HPV+HNSCC)相关的人乳头瘤病毒(HPV+HNSCC)的发病率在美国迅速上升。与非HPV相关性HNSCC相比，HPV+HNSCC具有不同的病因学、人口学和临床病理特征。然而，与其他实体肿瘤相比，HPV+HNSCC的治疗开发具有挑战性，因为靶向致癌基因突变的发生率很低，而且转录特征有限。对选择性RNA剪接事件(ASE)的研究，提供了对新的转录变化的洞察，并可以扩展HPV+HNSCC的转录特征。我们的项目将通过两个具体目标定义HPV+HNSCC特定的选择性剪接事件：(1)定义初级HPV+HNSCC中的差异选择性剪接，以及(2)验证HPV+HNSCC中的差异选择性剪接。我们将结合转录产物的高通量分析使用异常值分析来定义HPV+HNSCC特有的高价值ASE。我们将使用多个队列和互补的验证技术对检测到的ASE候选进行验证。该项目将提供对HPV+HNSCC生物学的洞察，并可能为HPV+HNSCC特异性治疗的开发提供治疗和预后靶点。在建议的R21奖项期间开发的数据将被用作R01奖励的初步数据，试图发现剪接事件的功能作用以及替代剪接与患者临床病理参数的相关性，以便开发 靶向HPV+HNSCC特异性ASES的翻译治疗及临床应用

 DESCRIPTION (provided by applicant): The incidence of Human Papilloma Virus related to head and neck squamous cell carcinoma (HPV+ HNSCC) is rapidly increasing in the United States. HPV+ HNSCC has distinct etiologic, demographic, and clinico- pathologic characteristics in comparison to non-HPV related HNSCC. However, the therapy development for HPV+ HNSCC is challenging due to a low incidence of targetable oncogenic mutations and limited transcriptional characterization in comparison to other solid tumors. The investigation of alternative RNA splicing events (ASEs), provides insight into novel transcription alterations, and can expand the transcriptional characterization of HPV+ HNSCC. Our project will define HPV+ HNSCC specific alternative splicing events via two specific aims: (1) Definition of differential alternative splicing in primary HPV+ HNSCC, and (2) Validation of differential alternative splicing in HPV+ HNSCC. We will use outlier analysis in combination with high throughput analysis of transcriptional products to define high value ASEs specific for HPV+ HNSCC. We will perform validation of detected ASE candidates using multiple cohort and complementary validation techniques. This project will provide insight into HPV+ HNSCC biology and will potentially provide therapeutic and prognostic targets for the development of HPV+ HNSCC specific therapies. The data developed during the proposed R21 award will be used as preliminary data for an R01 grant, seeking to discover the functional role of splicing events and correlation of alternative splicing with patient clinicopathological parameters in order to develop the translational therapeutic and clinical application of targeting HPV+ HNSCC specific ASEs.