Project 3-Human papillomavirus in HIV associated lung cancers

项目3-人类乳头瘤病毒在HIV相关肺癌中的作用

• 批准号: 10223350
• 负责人: Zhen Lin
• 金额: $ 28万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223350
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Cancer cell line; Cell Culture Techniques; Cells; Clinical; Copy Number Polymorphism; DNA; Data; Data Set; Detection; Disease Management; Environment; Epithelial Cells; Estrogen Receptor alpha; Etiology; Evaluation; Future; Gene Mutation; General Population; Genes; Genetic Transcription; Genomic DNA; Genomics; Goals; Growth; HIV; HPV-High Risk; Highly Active Antiretroviral Therapy; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Incidence; Individual; Induced Mutation; Infection; Informatics; Lung; Lung Neoplasms; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mutation; Nucleotides; Odds Ratio; Oncogenic; Oncology; Pathogenesis; Pathway interactions; Patient Care; Patients; Phenotype; Population; Reporting; Research; Rest; Risk Factors; Role; Sampling; Signal Transduction; Smoking; Smoking Status; Solid; Testing; Therapeutic; Time; Tissues; Transcript; Tumor Tissue; Variant; Viral; Viral Oncogene; Virus Integration; Work; base; cancer risk; driver mutation; established cell line; fusion gene; gene product; genome sequencing; human papilloma virus oncogene; improved; in vivo; infection rate; insertion/deletion mutation; insight; knock-down; lung cancer cell; lung carcinogenesis; mortality; power analysis; transcriptome; transcriptome sequencing; tumor; tumorigenesis; virome; whole genome

Abstract: In recent years, AIDS-related mortality has dramatically decreased due to the highly active antiretroviral therapy (HAART) but the mortality caused by the non-AIDS-defining cancers, especially lung cancer (LC) is continuously rising. In the U.S., LC becomes the most common and most deadly non-AIDS- defining cancer in HIV(+) populations. Although smoking is a key risk factor for HIV associated LCs, HIV(+) individuals still have a significantly increased LC risk after controlling for smoking status, indicating that other factors are responsible for the higher LC incidence in HIV(+) populations. Existing etiology studies have been largely focused on the involvement of human papillomavirus (HPV) in non-HIV associated LCs. A study to investigate the role of HPV in HIV associated LCs has not yet been reported. To date, the view on whether or not HPV is associated with LCs is highly controversial, since the observed HPV infection rate in LCs varies from 0 to 100%. Further, the hypothetic role of HPV in LCs is mainly based on the detection of HPV genomic DNA in LCs. So far, none of the association studies has demonstrated that the detected HPV DNA is transcriptionally active in the lung tumor tissues. Without evidence of viral transcription, the causal role of HPV in LCs is highly questionable, since it's well known that HPV must be transcriptionally active in order to induce its associated cancers. The overarching goal of this proposal is to resolve this long-standing controversy of the involvement of HPV in LCs using our cutting-edge sequencing and informatics approaches and information obtained from the natural in vivo tumor environment. To accomplish this goal, we will first examine our hypothesis that HPV is causally associated with a subset of LCs in HIV(+) population, but not in the general population. The rest of the work will test our hypothesis that HPV promotes lung oncogenesis by inducing a unique set of cancer driver mutations and manipulating cancer pathways through synergistic expression of viral E5 and E7 genes. By conducting the proposed work, we expect to get solid evidence supporting a causal role of HPV in HIV associated LCs and obtain much needed, unprecedented insight into the unique mechanism underlying the HPV(+) LCs in HIV infected individuals, which may be particularly significant for future patient care and disease management.

摘要：近年来，由于艾滋病防治工作的高度活跃，艾滋病相关死亡率急剧下降。 抗逆转录病毒治疗 (HAART)，但非艾滋病定义的癌症（尤其是肺癌）造成的死亡率 癌症（LC）持续上升。在美国，LC 成为最常见和最致命的非艾滋病 定义 HIV（+）人群中的癌症。尽管吸烟是 HIV 相关 LC 的一个关键危险因素，但 HIV(+) 在控制吸烟状况后，个体的 LC 风险仍然显着增加，这表明其他人 HIV（+）人群中 LC 发病率较高的因素。现有的病因学研究已 主要关注人乳头瘤病毒 (HPV) 在非 HIV 相关 LC 中的参与。一项研究 研究HPV在HIV相关LC中的作用尚未见报道。迄今为止，关于是否或 HPV 与 LC 是否相关存在很大争议，因为观察到 LC 中的 HPV 感染率各不相同 从 0 到 100%。此外，HPV在LC中的假设作用主要基于HPV基因组的检测 LC 中的 DNA。到目前为止，没有一项关联研究证明检测到的 HPV DNA 是 在肺肿瘤组织中转录活跃。没有病毒转录的证据，HPV 的因果作用 LC 中的 HPV 是非常值得怀疑的，因为众所周知，HPV 必须具有转录活性才能诱导 其相关的癌症。该提案的总体目标是解决这一长期存在的争议 使用我们的尖端测序和信息学方法和信息将 HPV 纳入 LC 从天然的体内肿瘤环境中获得。为了实现这个目标，我们首先要检查我们的 假设 HPV 与 HIV（+）人群中的一部分 LC 存在因果关系，但与一般人群无关 人口。其余的工作将检验我们的假设，即 HPV 通过诱导肺癌促进肺癌发生。 一组独特的癌症驱动突变并通过病毒的协同表达来操纵癌症途径 E5和E7基因。通过开展拟议的工作，我们期望获得支持因果作用的确凿证据 HIV 相关 LC 中的 HPV 的分析，并获得对独特机制急需的、前所未有的洞察 HIV 感染者的 HPV(+) LC 是潜在的，这对于未来的患者可能特别重要 护理和疾病管理。