Characterizing genome-wide alternative splicing in HPV related HNSCC

 描述（由申请方提供）：在美国，与头颈部鳞状细胞癌（HPV+ HNSCC）相关的人乳头瘤病毒的发病率正在迅速增加。与非HPV相关的HNSCC相比，HPV+ HNSCC具有不同的病因学、人口统计学和临床病理学特征。然而，HPV+ HNSCC的治疗开发具有挑战性，因为与其他实体瘤相比，可靶向致癌突变的发生率较低，转录特征有限。对可变RNA剪接事件（ASES）的研究提供了对新的转录改变的深入了解，并可以扩展HPV+ HNSCC的转录特征。我们的项目将通过两个特定的目标来定义HPV+ HNSCC特异性选择性剪接事件：（1）原发性HPV+ HNSCC中差异选择性剪接的定义，以及（2）HPV+ HNSCC中差异选择性剪接的验证。我们将使用离群值分析结合转录产物的高通量分析来确定HPV+ HNSCC特异性的高价值ASE。我们将使用多个队列和互补验证技术对检测到的ASE候选者进行验证。该项目将深入了解HPV+ HNSCC生物学，并可能为HPV+ HNSCC特异性疗法的开发提供治疗和预后靶点。在拟议的R21奖期间开发的数据将用作R01资助的初步数据，旨在发现剪接事件的功能作用以及选择性剪接与患者临床病理参数的相关性，以开发 靶向HPV+ HNSCC特异性ASES的转化治疗和临床应用。

 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.