Polyomavirus- Associated Human Cancers

描述(申请人提供)：虽然多瘤病毒可以在细胞培养和动物模型中诱导细胞转化，但它们在导致人类癌症方面的作用一直存在争议。该家族的一个新成员，命名为默克尔细胞多瘤病毒(MCV)，据报道是2008年初罕见的默克尔细胞癌(MCC)的潜在病原体。随后，来自北美、欧洲和澳大利亚的样本证实了MCV在MCC中的高发病率。MCV在8-16%的对照样本中出现，在胃肠道和皮肤的各种组织中的拷贝数非常低，而在默克尔细胞癌样本中的这一比例为80%。在其他已知的人类致癌病毒中也记录了这种现象。此外，许多致癌病毒会导致多种类型的癌症。例如，8型疱疹病毒(HHV-8)/卡波西氏肉瘤疱疹病毒(KSHV)会导致卡波西氏肉瘤、淋巴瘤和其他疾病。有趣的是，默克尔细胞癌和卡波西肉瘤有相似的流行病学特征。因此，我们假设除了默克尔细胞肿瘤外，MCV还与其他癌症有关。我们还想知道其他已知和未知的多瘤病毒是否也与癌症的发生有关。为了实现这些目标，我们将创建各种试剂和分析方法来确定人类多瘤病毒，特别是MCV在不同类型癌症中的参与情况。我们的具体目标是：1.发展MCV免疫分析方法，用于血清学研究；MCV特异性抗体，用于肿瘤免疫组织化学分析。2.用基于阵列的综合分析方法鉴定癌症中的多瘤病毒；3.采用病例对照设计，在一系列癌症中建立支持或反对MCV的初步血清流行病学证据。一旦确定了病毒的病因学作用，我们可能会将这种病毒用作诊断和预后的生物标记物，并作为潜在的治疗靶点。这些较长期的目标已经在其他致癌病毒中成功证明，如乙肝病毒和人乳头瘤病毒。 公共卫生相关性：与多瘤病毒相关的人类癌症最近发现的一种病毒，名为默克尔细胞多瘤病毒(MCV)，可能成为第七种真正的人类致癌病毒。这项研究的目的是调查这种病毒与各种类型癌症的相关性，并评估这种病毒作为诊断和预后标志物的用途。一个潜在的长期目标是开发一种针对MCV的癌症预防疫苗。

DESCRIPTION (provided by applicant): While polyomaviruses can induce cell transformation in cell culture and in animal models, their role in causing human cancers has been controversial. A new member of this family, named Merkel cell polyomavirus (MCV) was reported to be a potential etiological agent for the rare Merkel cell carcinoma (MCC) in early 2008. Subsequently, high incidence of MCV in MCC was confirmed with samples from North America, Europe and Australia. MCV appears to be present in 8-16% of control samples with very low copy number in various tissues of gastrointestinal tract and skin, compared to 80% of Merkel cell cancer samples. Such phenomenon is also documented in other known human oncogenic viruses. In addition, a number of oncogenic viruses cause more than one type of cancer. For example, herpesvirus-8 (HHV-8)/Kaposi's sarcoma herpesvirus (KSHV) causes Kaposi's sarcoma, lymphoma and other diseases. Interestingly, Merkel cell carcinoma and Kaposi's sarcoma share a similar epidemiological profile. Therefore, we hypothesize that MCV is also associated with other cancers in additional to the Merkel cell tumor. We are also interested in finding if the other known and unknown polyomaviruses are also associated with cancer development. To achieve these goals, we will create a variety of reagents and assays to determine the involvement of human polyomaviruses, particularly MCV, in different types of cancers. Our specific aims are 1. Developing MCV immunoassays for seroepidimiological studies and MCV-specific antibodies for cancer immunohistochemical analyses. 2. Identifying polyomaviruses in cancer with a comprehensive array-based assay; 3. Using a case-control design, establish preliminary seroepidemiologic evidence for or against MCV as a causal agent in a spectrum of cancers. Once establishing the etiological role of the virus, we will potentially use this virus as a diagnostic and prognostic biomarker and as a potential therapeutic target. These longer term goals have been successfully demonstrated in other oncogenic viruses, such as hepatitis B virus and human papillomaviruses. PUBLIC HEALTH RELEVANCE: Polyomavirus- Associated Human Cancers A recently discovered virus, named Merkel cell polyomavirus (MCV), may become the 7th bona fide human cancer-causing virus. This study aims to investigate the association of this virus and various types of cancer and to evaluate the use of this virus as a diagnostic and prognostic marker. A potential long term goal is to develop a vaccine targeting MCV for cancer prevention.