Characterizing genome-wide alternative splicing in HPV related HNSCC

HPV 相关 HNSCC 中全基因组选择性剪接的特征

• 批准号: 9099807
• 负责人: Daria A Gaykalova
• 金额: $ 20.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099807
• 关键词: Affect; Alcohols; Alternative Splicing; Biological Assay; Biology; Characteristics; DNA Sequence Alteration; Data; Detection; Development; Diagnosis; Disease; Down-Regulation; Epigenetic Process; Event; Exons; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Exposure to; Future; Genes; Genetic; Goals; Grant; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Health; Heterogeneity; Human Papillomavirus; Human papilloma virus infection; Incidence; Investigation; Lead; Liquid substance; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mutation; Normal tissue morphology; Oncogenes; Oncogenic; Oropharyngeal; Pathologic; Pathway interactions; Patients; Pilot Projects; Play; Population; Proto-Oncogene Proteins c-akt; Public Health; RNA Splicing; Role; Sampling; Solid; Solid Neoplasm; Staging; TP53 gene; Techniques; The Cancer Genome Atlas; Therapeutic; Time; Tobacco; Transcript; Transcription Alteration; Tumor Suppressor Proteins; United States; Up-Regulation; Validation; Variant; Woman; biomarker development; cancer cell; candidate validation; cell transformation; clinical application; cohort; design; differential expression; genome-wide; genome-wide analysis; high risk; high throughput analysis; improved; insight; male; men; new therapeutic target; non-smoking; novel; outcome forecast; prognostic; protein expression; response; specific biomarkers; targeted treatment; therapy development; transcriptome sequencing; tumor

 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.

 描述（由适用提供）：在美国，人类乳头状瘤病毒与头颈部鳞状细胞癌（HPV+ HNSCC）有关的事件正在迅速增加。与非HPV相关的HNSCC相比，HPV+ HNSCC具有不同的病因，人口统计学和临床​​ - 病理特征。然而，由于与其他实体瘤相比，HPV+ HNSCC的治疗开发因靶向致癌突变的低入射和有限的转录表征而具有挑战性。替代RNA剪接事件（ASE）的投资提供了对新的转录改变的见解，并可以扩大HPV+ HNSCC的转录表征。我们的项目将通过两个特定目的定义HPV+ HNSCC特定的替代剪接事件：（1）定义主HPV+ HNSCC中的差分替代剪接，以及（2）验证HPV+ HNSCC中差分替代剪接的验证。我们将使用异常分析与转录产品的高吞吐量分析结合使用，以定义针对HPV+ HNSCC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。该项目将提供有关HPV+ HNSCC生物学的见解，并有可能为HPV+ HNSCC特定疗法的开发提供治疗和预后靶标。在拟议的R21奖励期间开发的数据将用作R01赠款的初步数据，旨在发现剪接事件的功能作用以及替代剪接与患者临床病理学参数的相关性 靶向HPV+ HNSCC特定ASE的翻译治疗和临床应用。