Molecular origin and evolution of HPV inactive head and neck cancers

HPV 不活跃头颈癌的分子起源和进化

• 批准号: 9188009
• 负责人: LUCIA Amelia PIRISI-CREEK
• 金额: $ 14.52万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9188009
• 关键词: Alcohol consumption; Behavioral; Biological Models; Breast; Cancer Etiology; Cell Cycle; Cell Proliferation; Cells; Cervix Uteri; Characteristics; Chromogenic in situ Hybridization; Classification; Clinical; DNA; DNA Methylation; Dependence; Detection; Diagnostic; Disease; Disputes; Effectiveness; Epidemiology; Epigenetic Process; Esophagus; Evaluation; Event; Evolution; Exhibits; Freezing; Future; Gene Expression; Genes; Genetic; Genital system; Genomics; Growth; Head and Neck Cancer; Histologic; Hospitals; Human; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papillomavirus 16; In Situ; In Vitro; Lead; Lesion; Light; Link; Lung; Malignant Neoplasms; Maps; Mediating; Methods; Molecular; Molecular Profiling; Mutation; Oncoproteins; Oral; Oropharyngeal; Pathogenesis; Pathway interactions; Patients; Pattern; Population; Premalignant; Prevention; Proteins; RNA; Rectum; Reporting; Risk Factors; Role; Sampling; Series; Sex Behavior; Signal Transduction; Site; Smoking; Staining method; Stains; Surrogate Markers; Survival Rate; TP53 gene; Testing; Time; Transcript; Tumor Tissue; Undifferentiated; Work; angiogenesis; cancer site; carcinogenesis; cell motility; cell transformation; clinically relevant; cohort; head and neck cancer prevention; in vitro Model; keratinocyte; malignant oropharynx neoplasm; mutational status; novel; outcome forecast; public health relevance; tumor

 DESCRIPTION (provided by applicant): Head and neck cancers are positive for human papillomavirus (HPV) in about 25% of the cases overall, and in up to 60% of the cases at specific sites, such as the oropharynx. A causal role of HPV (in particular HPV16) in the pathogenesis of oropharyngeal cancer (OPC) is now well accepted, as it is clear that HPV- positive cancers that are "driven" by the oncoproteins E6 and E7 constitute a disease of their own, with specific histological, molecular, clinical and epidemiological characteristics. HPV-positive tumors that exhibit E6/E7 expression (the surrogate marker for this is positive p16 staining) occur in younger patients; are more likely to be basaloid and relatively undifferentiated exhibit gene expression profiles in dicative of alterations of cell cycle and proliferation-related gene pathways; are not linked to alcohol consumption or smoking; and are linked to specific sexual behaviors. These tumors have a better prognosis than the HPV-negative tumors, which are epidemiologically linked to smoking and alcohol consumption and (according to our preliminary results, as well as other reports) exhibit gene expression profiles that are indicative of profound alterations of mechanisms of EMT, angiogenesis, and cell motility. We and others have shown that OPC from Black patients are often HPV-negative, while the HPV-positive cancers occur primarily in White patients. In addition, we have recently determined that HPV-positive OPC in Black patients are more often HPV-inactive: these tumors contain HPV DNA but do not express HPV oncoproteins and are p16-negative. We have shown that HPV-inactive tumors have gene expression profiles and survival rates similar to those of HPV-negative tumors. It is commonly assumed that in HPV-inactive tumors HPV is a "passenger" and has no role in their pathogenesis, however there are no studies corroborating or disputing this interpretation. We propose here the alternative and novel hypothesis that HPV-inactive tumors may start as HPV-driven lesions, at either pre- malignant or early invasive stages, and then "turn" to an HPV-inactive status by either mutational or epigenetic events. If our hypothesis is proven correct, this would represent a completely novel mechanism for HPV-mediated carcinogenesis that would cause us to re-think how HPV may cause cancer at sites other than the cervix. This application investigates the proposed hypothesis by two specific aims: 1) to analyze, by in situ methods of detection of HPV transcripts, the HPV expression status of a series of OPC cases positive for HPV-DNA in which the tumor mass is heterogeneous in terms of p16 expression; 2) to investigate potential mechanisms of "escape" from HPV control of growth in a model system for HPV16-mediated transformation in vitro. The results of these studies will clarify the role of HPV in OPC; allow for a more precise classification of OPC and HNC; and influence our evaluation of the effectiveness of HPV vaccines in the prevention of HNC. In addition, these results, if positive, would prompt a re-evaluation of the role of HPV at other cancer sites (i.e. lung, breast esophagus and rectum).

 描述（由申请人提供）：头颈癌总体中约 25% 的病例呈人乳头状瘤病毒 (HPV) 阳性，在特定部位（例如口咽部）的病例中，高达 60% 的病例呈人乳头瘤病毒 (HPV) 阳性。 HPV（特别是 HPV16）在口咽癌（OPC）发病机制中的因果作用现已被广泛接受，因为很明显，由癌蛋白 E6 和 E7“驱动”的 HPV 阳性癌症构成了一种自身的疾病，具有特定的组织学、分子、临床和流行病学特征。表现出 E6/E7 表达（其替代标记是 p16 染色阳性）的 HPV 阳性肿瘤发生在年轻患者中；更有可能是基底细胞样且相对未分化，表现出指示细胞周期和增殖相关改变的基因表达谱 基因途径；与饮酒或吸烟无关；并与特定的性行为有关。这些肿瘤比 HPV 阴性肿瘤有更好的预后，HPV 阴性肿瘤在流行病学上与吸烟和饮酒有关，并且（根据我们的初步结果以及其他报告）表现出指示性的基因表达谱 EMT、血管生成和细胞运动机制的深刻改变。我们和其他人已经证明，黑人患者的 OPC 通常 HPV 阴性，而 HPV 阳性癌症主要发生在白人患者中。此外，我们最近确定，黑人患者中的 HPV 阳性 OPC 通常是 HPV 不活跃的：这些肿瘤含有 HPV DNA，但不表达 HPV 癌蛋白，且 p16 阴性。我们已经证明，HPV 不活跃的肿瘤具有与 HPV 阴性肿瘤相似的基因表达谱和存活率。人们普遍认为，在 HPV 不活跃的肿瘤中，HPV 是“乘客”，在其发病机制中没有任何作用，但没有研究证实或质疑这种解释。我们在这里提出了另一种新的假设，即 HPV 不活跃的肿瘤可能在癌前或早期侵袭阶段以 HPV 驱动的病变开始，然后通过突变或表观遗传事件“转变”为 HPV 不活跃状态。如果我们的假设被证明是正确的，这将代表一种全新的 HPV 介导的致癌机制，这将使我们重新思考 HPV 如何在宫颈以外的部位引起癌症。本申请通过两个具体目的研究了所提出的假设：1）通过原位检测 HPV 转录本的方法，分析一系列 HPV-DNA 呈阳性的 OPC 病例的 HPV 表达状态，其中肿瘤块在 p16 表达方面存在异质性； 2) 在HPV16介导的体外转化模型系统中研究“逃脱”HPV控制生长的潜在机制。这些研究结果将阐明 HPV 在 OPC 中的作用；允许对 OPC 和 HNC 进行更精确的分类；并影响我们对 HPV 疫苗预防 HNC 有效性的评估。此外，如果这些结果呈阳性，将促使人们重新评估 HPV 在其他癌症部位（即肺癌、乳腺食管和直肠）中的作用。