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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：
10523104
负责人：
Jin Zhang
金额：
$ 14.73万
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/10523104
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 Chemotherapy and/or radiation Clinical Clinical Data Code Complementary DNA Complex Computing Methodologies Data Data Analyses Development 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 Papillomavirus Transforming Protein E6 Patient-Focused Outcomes Patients Predisposition Prognosis Prognostic Factor Quantitative Reverse Transcriptase PCR RNA RNA-Directed DNA Polymerase Radiation Tolerance Recurrence Recurrent disease Regional Lymph Node Involvement 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 cellular engineering cervical carcinogenesis chemoradiation clinical research site cohort 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.

项目总结/文摘