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.

项目摘要/摘要人乳头瘤病毒（HPV）感染是宫颈癌的主要原因。局部先进的宫颈癌症（LACC）是无法治愈的，在护理标准化学放疗治疗（CRT）后的复发率很高。高风险的HPV基因型已经发展出复杂的调节策略，以严格控制病毒基因表达和替代剪接。最近的研究表明，某些剪接的HPV基因具有不同的与全长癌基因相比，宫颈肿瘤复制和肿瘤发生的功能。比率全长和剪接的HPV转录本可能在具有不同的高风险的宫颈肿瘤中变化 HPV基因型。我们手动检查了整个转录组测序（RNA-seq）数据并发现了复发性的HPV-Human基因融合，含有剪接的HPV转录本和较长的基因间非 - 蛋白质编码人RNA（lncRNA）。 HPV替代剪接在宫颈癌生物学中很重要。但是，目前尚不清楚是否剪接的HPV转录本是否影响宫颈癌患者。拟议的研究将确定是否剪接的HPV转录本是否对宫颈癌的患者结局具有预后和机械意义。具体来说，我们会的确定使用HPV转换的剪接的HPV转录物是否会调节辐射响应宫颈癌细胞和端粒酶 - 逆转录酶（HTERT）转化了宫颈上皮细胞。我们还将评估是否可以剪接的HPV转录本可以用作不同HPV的生物标志物使用cDNA捕获测序数据和临床数据的基因型来自已建立的LACC患者的临床数据用治愈性CRT均匀处理。最后，我们将开发新型算法以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。成功的这项翻译研究的完成将确定剪接的HPV转录本为准确 LACC中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辐射反应中的HPV替代剪接将最终促进优化疗法并改善患者预后。