Molecular origin and evolution of HPV inactive head and neck cancers

 描述(申请人提供)：在所有病例中，大约25%的头颈癌患者的人类乳头瘤病毒(HPV)呈阳性，在特定部位，如口咽部，高达60%的病例呈阳性。HPV(尤其是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阳性癌症本身就是一种疾病，具有特定的组织学、分子、临床和流行病学特征。HPV阳性肿瘤表现为E6/E7表达(替代标记为p16染色阳性)发生在较年轻的患者中；更可能是碱性细胞样且相对未分化的肿瘤表现出与细胞周期和增殖相关的改变的基因表达谱 基因途径；与饮酒或吸烟无关；与特定的性行为有关。这些肿瘤比HPV阴性的肿瘤预后更好，后者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和其他报告)表现出具有指示性的基因表达谱。 EMT、血管生成和细胞运动机制的深刻变化。我们和其他人已经证明，黑人患者的OPC通常是HPV阴性的，而HPV阳性的癌症主要发生在白人患者身上。此外，我们最近确定，黑人患者中HPV阳性的OPC更多的时候是HPV非活动性的：这些肿瘤含有HPV DNA，但不表达HPV癌蛋白，p16阴性。我们已经证明，HPV非活动性肿瘤具有与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是一种“乘客”，在其发病机制中没有任何作用，然而，没有研究证实或质疑这一解释。我们在这里提出了另一种新的假设，即HPV不活跃的肿瘤可能开始于HPV驱动的病变，无论是在癌前阶段还是早期侵袭阶段，然后通过突变或表观遗传事件“转变”到HPV非活跃状态。如果我们的假设被证明是正确的，这将代表着一种全新的HPV介导的致癌机制，它将促使我们重新思考HPV如何在宫颈以外的部位导致癌症。本申请通过两个特定的目的来研究提出的假说：1)通过原位检测HPV转录本的方法，分析一系列HPV-DNA阳性的OPC病例的HPV表达状况，在这些病例中，肿瘤块在p16表达方面是不同的；2)在体外HPV16介导的转化的模型系统中，研究“逃避”HPV对生长的控制的潜在机制。这些研究的结果将澄清HPV在OPC中的作用；允许对OPC和HNC进行更准确的分类；并影响我们对HPV疫苗预防HNC有效性的评估。此外，这些结果如果呈阳性，将促使重新评估HPV在其他癌症部位(即肺癌、乳腺癌、食道和直肠)的作用。

 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).