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HPV alternative splicing in cervical cancer radiation response

HPV选择性剪接在宫颈癌放射反应中的作用

基本信息

批准号：
10308435
负责人：
Jin Zhang
金额：
$ 15.67万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308435
关键词：
Affect Algorithms Alternative Splicing Biological Markers Cancer Biology Cancer Etiology Cancer Patient Cancer cell line Cause of Death Cervical Cervix Neoplasms Cervix carcinoma Clinical Clinical Data Code Complementary DNA Complex Computing Methodologies Data Data Analyses Development Disease Engineering Epithelial Cells Exons Future Gene Expression Gene Fusion Genes Genetic Transcription Genotype Goals HPV-High Risk Human Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 Human papillomavirus 18 In Vitro Length Link Malignant Neoplasms Malignant neoplasm of cervix uteri Manuals Measures Messenger RNA Oncogenes Outcome Patient-Focused Outcomes Patients Predisposition Prognosis Prognostic Factor Quantitative Reverse Transcriptase PCR RNA RNA-Directed DNA Polymerase Radiation Tolerance Recurrence Research Retinoblastoma Protein Role Sampling Spices TP53 gene Telomerase Testing Transcript Translational Research Tumor Bank Tumor Suppressor Proteins Viral Viral Genes Viral Oncogene Virus Work cancer cell cancer diagnosis cell transformation cervical carcinogenesis chemoradiation clinical research site cohort draining lymph node experience experimental study gene function improved in vivo innovation irradiation molecular marker novel prognostic prospective radiation response response standard of care therapy outcome tool transcriptome sequencing treatment optimization treatment response tumor tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Human papillomavirus (HPV) infection is the primary cause of cervical carcinoma. Locally advanced cervical cancer (LACC) is incurable with a high recurrence rate after standard-of-care chemoradiation therapy (CRT). High-risk HPV genotypes have evolved complex regulatory strategies to tightly control viral gene expression and alternative splicing. Recent studies indicate that some alternatively spliced HPV genes have different functions in cervical tumor replication and oncogenesis than their full-length oncogene counterparts. The ratio of full-length and alternatively spliced HPV transcripts can vary in cervical tumors harboring different high-risk HPV genotypes. We manually inspected whole transcriptome sequencing (RNA-seq) data and discovered recurrent HPV-human gene fusions containing alternatively spliced HPV transcripts and long intergenic non- protein-coding human RNAs (lncRNA). HPV alternative splicing is important in cervical cancer biology; however, it is still unclear whether alternatively spliced HPV transcripts affect the chemoradiation response in cervical cancer patients. The proposed research will determine whether alternatively spliced HPV transcripts have prognostic and mechanistic significance for patient outcomes in cervical cancer. Specifically, we will determine whether alternatively spliced HPV transcripts modulate radiation response using HPV-transformed cervical cancer cells and telomerase-reverse-transcriptase (hTERT) transformed cervical epithelial cells. We will also evaluate whether alternatively spliced HPV transcripts can serve as biomarkers for different HPV genotypes using cDNA capture sequencing data and clinical data from an established cohort of LACC patients uniformly treated with curative-intent CRT. Finally, we will develop novel algorithms to identify viral-host gene fusions and examine their functional consequences using RNA-seq data and clinical outcome data. Successful completion of this translational research will identify alternatively spliced HPV transcripts as accurate prognostic molecular biomarkers and suitable novel targets in LACC. Establishing the mechanistic function of HPV alternative splicing in cervical cancer radiation response will ultimately facilitate the development of optimized therapies and improve patient outcomes.

项目概要/摘要人乳头瘤病毒（HPV）感染是宫颈癌的主要原因。局部晚期颈椎病癌症（LACC）无法治愈，在标准放化疗（CRT）后复发率很高。高危 HPV 基因型已进化出复杂的调控策略来严格控制病毒基因表达和选择性剪接。最近的研究表明，一些选择性剪接的 HPV 基因具有不同的其在宫颈肿瘤复制和肿瘤发生中的功能优于其全长癌基因对应物。比率具有不同高风险的宫颈肿瘤中全长和选择性剪接的 HPV 转录本可能有所不同 HPV 基因型。我们手动检查了全转录组测序 (RNA-seq) 数据并发现复发性 HPV-人类基因融合体包含选择性剪接的 HPV 转录物和长基因间非蛋白质编码人类 RNA (lncRNA)。 HPV 选择性剪接在宫颈癌生物学中很重要；然而，目前尚不清楚可变剪接的 HPV 转录本是否会影响放化疗反应。宫颈癌患者。拟议的研究将确定 HPV 转录物是否存在选择性剪接对宫颈癌患者的预后具有预后和机制意义。具体来说，我们将使用 HPV 转化确定选择性剪接的 HPV 转录本是否调节辐射反应宫颈癌细胞和端粒酶逆转录酶（hTERT）转化的宫颈上皮细胞。我们还将评估选择性剪接的 HPV 转录本是否可以作为不同 HPV 的生物标志物使用 cDNA 捕获测序数据和来自已建立的 LACC 患者队列的临床数据进行基因分型统一采用治疗性 CRT 治疗。最后，我们将开发新的算法来识别病毒宿主基因融合并使用 RNA-seq 数据和临床结果数据检查其功能后果。成功的完成这项转化研究将确定选择性剪接的 HPV 转录本是准确的 LACC 的预后分子生物标志物和合适的新靶标。建立机械功能宫颈癌放射反应中的HPV选择性剪接最终将促进宫颈癌的发展优化治疗并改善患者治疗效果。