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.

项目摘要/摘要 将人乳头瘤病毒（HPV）整合到宿主基因组中是主要特征 侵入性宫颈癌（ICC）。积分位点的基因组坐标已在 许多肿瘤，但对这些位点的顺式基因组变化的性质知之甚少，或 他们如何促进ICC。沿着癌症基因组图集（TCGA）利用数据 随着患者匹配的HPV集成位点的长阅读测序将定义新颖 影响ICC结果的基因/途径。 AIM 1将定义TCGA-中的HPV集成位点 MCW宫颈癌队列使用新开发的HPV DNA捕获进行长阅读测序。 一旦确定，我们将使用记录的TCGA数据源注释每个集成站点 复杂的重排，拷贝数变化，克隆性，杂合性丧失，表观遗传 签名，基因表达和嵌合。由此内部发现的集成位点的特征 深度注释将使我们能够优先考虑推定的集成驱动程序基因 在AIM 2中，当我们确定受高度影响的一些基因的生物学相关性 优先级HPV集成站点。然后，我们将使用一系列可用的宫颈癌细胞系 表征操纵功能中的基因的功能后果 宫颈癌尚未确定。拟议的研究有望确定 特定HPV整合位点的下游分子驱动器，从而揭示了新型ICC特异性 可以针对治疗的治疗脆弱性。