Novel Pathogen Associated Cancers (PQ12)

描述（由申请人提供）：世界上近20%的癌症负担可归因于慢性传染病。大多数感染相关的癌症已被证明具有病毒病因，尽管细菌和寄生虫也有助于全球癌症负担。所有已知的病毒相关癌症在免疫抑制个体中特异性增加，并且还有其他可能具有病毒病因的癌症，因为它们也在免疫抑制后增加。淋巴瘤，肛门生殖器恶性肿瘤和肺癌已被发现是越来越常见的一组不同的免疫抑制个体。我们建议在本申请中鉴定最可能归因于感染的那些癌症的病毒病因。具体来说，我们将集中在淋巴瘤的子集，更常见于免疫抑制的个人，但并没有一贯相关的爱泼斯坦巴尔病毒（霍奇金淋巴瘤和弥漫性大B细胞淋巴瘤），近50%的阴茎和外阴癌没有归因于人乳头瘤病毒（HPV）感染，和多种肺癌在一个年轻的免疫抑制人群与烟草接触有限。我们的总体策略将是从在多种免疫抑制人群中显著增加的癌症中获得样本，对肿瘤转录组进行高通量测序和计算分析以鉴定病毒序列，开发检测方法以确定病毒是否通常与癌症相关，使用记录良好的病例对照系列，并以默克尔细胞多瘤病毒（MCPyV）为例，开始研究病毒致癌机制。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人员团队，他们将获得来自乌干达艾滋病毒感染者的独特肿瘤标本，以及来自美国的艾滋病毒阴性乌干达人和移植队列的验证。 公共卫生相关性：在预防或治疗我们已知具有传染性病因的癌症方面取得了巨大进展，例如开发分别预防肝癌和肛门生殖器癌的HBV和HPV疫苗，以及用抗病毒药物治疗各种淋巴瘤。其他癌症很可能具有感染性病因，识别新的关联将对癌症的早期诊断、治疗和预防产生重大影响。

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. PUBLIC HEALTH RELEVANCE: There has been tremendous progress in preventing or treating cancers that we know have an infectious etiology, such as developing HBV and HPV vaccines to prevent liver and anogenital cancers respectively, and treating a variety of lymphomas with antivirals. It is likely that other cancers have an infectious etiology and identifying new associations would have a significant impact on early diagnosis, treatment, and prevention of cancer.