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，由于高度活跃，与AIDS相关的死亡率已大大降低 抗逆转录病毒疗法（HAART），但由定义的癌症，尤其是肺部造成的死亡率 癌症（LC）不断增加。在美国，LC成为最常见，最致命的非辅助 - 定义HIV（+）种群中的癌症。尽管吸烟是HIV相关LC的关键危险因素，但HIV（+） 在控制吸烟状态后，个人仍然有明显增加的LC风险，表明其他 因素是艾滋病毒（+）种群中LC发病率较高的原因。现有的病因研究已经 主要集中于人类乳头瘤病毒（HPV）在非HIV相关LC中的参与。研究 研究HPV在HIV相关LC中的作用尚未报道。迄今为止，关于是否或 不与LCS相关的HPV是高度争议的，因为观察到的LCS中的HPV感染率有所不同 从0到100％。此外，HPV在LCS中的假设作用主要基于HPV基因组的检测 LCS中的DNA。到目前为止，尚未进行关联研究表明检测到的HPV DNA是 在肺肿瘤组织中具有转录活性。没有病毒转录的证据，HPV的因果作用 在LC中是高度可疑的，因为众所周知，HPV必须具有转录活性才能诱导 它相关的癌症。该提议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，HPV参与LCS 从天然体内肿瘤环境获得。为了实现这一目标，我们将首先检查我们的 假设HPV与HIV（+）种群中LC的一部分有因果关系，但在一般 人口。其余的工作将检验我们的假设，即HPV通过诱导A促进肺部肿瘤发生 独特的癌症驱动器突变和通过病毒的协同表达来操纵癌症途径 E5和E7基因。通过进行拟议的工作，我们希望获得支持因果角色的可靠证据 HPV与HIV相关的LCS的HPV，并获得了急需的，前所未有的洞察力 艾滋病毒感染者的HPV（+）LCS的基础，这对未来的患者可能尤其重要 护理和疾病管理。