Defining HPV integration sites of unknown significance in invasive cervical cancer

定义浸润性宫颈癌中意义不明的 HPV 整合位点

• 批准号: 10042465
• 负责人: Janet S. Rader
• 金额: $ 40.11万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10042465
• 关键词: Address; Affect; Alleles; Antigens; Biological; Biological Assay; Cancer Patient; Cancer cell line; Candidate Disease Gene; Capsid; Cell Line; Cessation of life; Characteristics; Chimerism; Clinical; Clonality; Complex; Consult; Copy Number Polymorphism; DNA; DNA Methylation; Data; Data Sources; Disease Progression; Epigenetic Process; Event; Female; Future; Gene Expression; Generations; Genes; Genome; Genomics; Goals; Human Genome; Human Papilloma Virus Vaccine; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; In Vitro; Individual; Knowledge; Loss of Heterozygosity; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mediating; Minority Groups; Modeling; Modification; Molecular; Mutate; Nature; Nucleic Acid Regulatory Sequences; Oncogenes; Outcome; PVT1 gene; Pathway interactions; Patients; Phase; Protein Array; RNA; Research; Resolution; Role; Sampling; Site; Small Interfering RNA; Structure; Technology; Testing; The Cancer Genome Atlas; Therapeutic; Transcript; Treatment outcome; Update; Viral; Virus Diseases; Woman; basonuclin; cancer survival; carcinogenesis; cervical carcinogenesis; clinically relevant; cohort; experience; genome sequencing; improved; in silico; individualized medicine; innovation; integration site; knock-down; malignant phenotype; meetings; miRNA expression profiling; multidimensional data; new therapeutic target; novel; novel therapeutic intervention; overexpression; patient stratification; personalized medicine; prevent; promoter; reproductive; socioeconomics; targeted treatment; transcriptome sequencing; tumor; tumor DNA; tumor progression; whole genome; years of life lost

PROJECT SUMMARY/ABSTRACT Integration of the human papillomavirus (HPV) into the host genome is a dominant feature of invasive cervical cancer (ICC). Genomic coordinates of integration sites have been identified in many tumors, but little is known about the nature of the cis genomic changes at these sites or how they might promote ICC. Harnessing data from The Cancer Genome Atlas (TCGA) along with patient-matched long-read sequencing of HPV integration sites will define novel genes/pathways affecting ICC outcome. Aim 1 will define HPV integration sites in the TCGA- MCW cervical cancer cohort using newly developed HPV DNA capture for long-read sequencing. Once identified, we will annotate each integration site using TCGA data sources that document complex rearrangements, copy number variation, clonality, loss-of-heterozygosity, epigenetic signature, gene expression, and chimerism. Characteristics of integration sites found by this in- depth annotation will enable us to prioritize putative integration driver genes to be further studied in Aim 2, when we will establish the biological relevance of a few genes influenced by our high- priority HPV integration sites. Using a panel of available cervical cancer cell lines, we will then characterize the functional consequences of manipulating those genes whose functions in cervical cancer have yet to be determined. The proposed study is expected to identify downstream molecular drivers of specific HPV integration sites, thus revealing novel ICC-specific therapeutic vulnerabilities that may be targeted for treatment.

项目总结/摘要 人乳头瘤病毒（HPV）整合到宿主基因组中是HPV感染的主要特征。 浸润性宫颈癌（ICC）。整合位点的基因组坐标已在 许多肿瘤，但很少有人知道在这些网站的顺式基因组变化的性质，或 如何促进国际刑事法院。利用癌症基因组图谱（TCGA）的数据，沿着 HPV整合位点的患者匹配长读序测序将定义新的 影响ICC结果的基因/途径。目标1将在TCGA中定义HPV整合位点- MCW宫颈癌队列使用新开发的HPV DNA捕获进行长读序。 一旦确定，我们将使用记录以下内容的TCGA数据源对每个集成站点进行注释： 复杂重排，拷贝数变异，克隆性，杂合性缺失，表观遗传 特征、基因表达和嵌合体。通过这种方法发现的整合位点的特征- 深度注释将使我们能够优先考虑推定的整合驱动基因进行进一步研究 在目标2中，当我们将建立一些基因的生物学相关性时，我们的高- 优先HPV整合位点。使用一组可用的宫颈癌细胞系，我们将 描述操纵这些基因的功能后果，这些基因的功能在 子宫颈癌尚未确定。拟议的研究预计将确定 特异性HPV整合位点的下游分子驱动因子，从而揭示了新的ICC特异性 可能成为治疗目标的治疗弱点。