Novel Pathogen Associated Cancers (PQ12)

描述(申请人提供)：世界上近20%的癌症负担可归因于慢性传染病。大多数与感染相关的癌症都被证明是由病毒引起的，尽管细菌和寄生虫也会造成全球癌症负担。所有已知的病毒相关癌症在免疫抑制的个体中都有特定的增加，还有其他癌症可能有病毒病因，因为它们在免疫抑制后也会增加。淋巴瘤、肛门恶性肿瘤和肺癌在不同的免疫抑制人群中越来越常见。我们建议在这一应用中确定最可能归因于感染的癌症的病毒病因学。具体地说，我们将关注在免疫抑制个体中更常见但与Epstein Barr病毒(霍奇金淋巴瘤和弥漫性大B细胞淋巴瘤)并不一致相关的淋巴瘤亚群，近50%的阴茎和外阴癌未归因于人类乳头瘤病毒(HPV)感染，以及在免疫抑制的年轻人群中有限接触烟草的各种肺癌。我们的总体战略将是从在多个免疫抑制人群中显著增加的癌症中获取样本，对肿瘤转录本进行高通量测序和计算分析以确定病毒序列，利用有据可查的病例对照系列开发分析以确定病毒是否通常与癌症有关，并开始以默克尔细胞多瘤病毒(MCPyV)为例研究病毒致癌的机制。我们汇集了一支在癌症生物学、传染病、病毒发现、计算生物学和流行病学方面具有互补专业知识的研究团队，他们将能够获得来自乌干达艾滋病毒感染者的独特肿瘤样本，以及在艾滋病毒阴性的乌干达人和来自美国的移植队列中进行验证。

DESCRIPTION (provided by applicant): Nearly twenty percent of the world's cancer burden can be attributed to chronic infectious diseases. Most infection-associated cancers have been shown to have a viral etiology, though bacteria and parasites also contribute to the global cancer burden. All known virus-associated cancers are specifically increased among immunosuppressed individuals, and there are other cancers that likely have a viral etiology because they too are increased following immunosuppression. Lymphoma, anogenital malignancies and lung cancer have been found to be increasingly common in a diverse set of immunosuppressed individuals. We propose to identify a viral etiology of those cancers most likely attributable to infection in this application. Specifically, we will focus on the subset of lymphomas that are more common in immunosuppressed individuals but have not been consistently related to Epstein Barr Virus (Hodgkin lymphoma and diffuse large B-cell lymphoma), the nearly 50% of penile and vulvar cancers that have not been attributed to infection with human papillomavirus (HPV), and a wide variety of lung cancers in a young immunosuppressed population with limited exposure to tobacco. Our overall strategy will be to obtain samples from cancers that are significantly increased in multiple immunosuppressed populations, to perform high throughput sequencing of tumor transcriptomes and computational analyses to identify viral sequences, to develop assays to determine whether the viruses are generally associated with cancers using well documented case-control series, and to begin to investigate the mechanisms of viral carcinogenesis using Merkel Cell polyomavirus (MCPyV) as an example. We bring together a team of investigators with complementary expertise in cancer biology, infectious diseases, virus discovery, computational biology and epidemiology, which will have access to unique tumor specimens originating from individuals with HIV infection in Uganda as well as validation in HIV-negative Ugandans and transplant cohorts from the United States.