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（由适用提供）：在大约25％的整体病例中，头颈癌对人乳头瘤病毒（HPV）呈阳性，在特定地点（例如口咽）中，多达60％的病例是阳性的。现在，HPV（特别是HPV16）在口咽癌（OPC）的发病机理中的因果作用已被广泛接受，因为很明显，由Oncoproteins E6和E7“驱动”的HPV-阳性癌症构成了特定的组织学，分子，临床，临床，临床和典型学特征。暴露于E6/E7表达的HPV阳性肿瘤（替代标记为阳性P16染色）发生在年轻患者中。在细胞周期变化和增殖相关的指示中，更可能是基础基础，并且相对于展示基因表达谱。 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阴性肿瘤具有更好的预后，这些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道）暴露了基因表达曲线，这是指示性的 EMT，血管生成和细胞运动机制的深刻改变。我们和其他人表明，来自黑人患者的OPC通常是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的HPV阳性OPC更常见于HPV触发性：这些肿瘤含有HPV DNA，但不表达HPV癌蛋白，并且是p16阴性。我们已经表明，HPV可能的肿瘤具有与HPV阴性肿瘤相似的基因表达谱和存活率。通常认为，在HPV不可能的肿瘤中，HPV是“乘客”，在其发病机理中没有作用，但是没有研究证实或争论这种解释。我们在这里提出了一种替代性和新颖的假设，即HPV不活跃的肿瘤可能以HPV驱动的病变开始，无论是在恶性前还是早期入侵阶段，然后通过突变事件或表观遗传事件“转动”到HPV-Inactive状态。如果我们的假设被证明是正确的，这将代表HPV介导的癌变的完全新颖的机制，这将使我们重新考虑HPV如何在子宫颈以外的其他部位引起癌症。该申请通过两个具体目的研究了提出的假设：1）通过原位检测HPV转录本的原位方法，HPV表达的HPV表达状态是HPV-DNA呈阳性的一系列OPC病例，其中肿瘤质量在P16表达方面是异构的； 2）研究在体外HPV16介导的模型系统中，从HPV控制的HPV控制中“逃脱”的潜在机制。这些研究的结果将阐明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的有效性的评估。此外，如果阳性，这些结果将促使HPV在其他癌症部位（即肺，乳腺食道和直肠）重新评估。