Nested case-control study of JC virus infection and incident colorectal cancer

描述(申请人提供)：JC病毒(JCV)，一种常见的人类多瘤病毒感染，已被认为是结直肠癌的潜在危险因素。有几条实验室证据支持JCV在结直肠癌早期发展中的作用。不幸的是，还没有关于过去感染JCV与结直肠癌之间关系的流行病学研究。我们建议对马里兰州华盛顿县两个社区队列中嵌套的JCV和偶发结直肠癌的循环诊断前抗体进行配对病例对照研究。本研究的目的是确定JC病毒感染与结直肠癌之间的关系，以便制定未来的预防策略。具体地说，我们的目标是检测582例结直肠癌、135例癌前腺瘤性息肉和1,299名匹配对照的诊断前血清中JCV衣壳和癌蛋白的抗体水平，以确定JCV抗体血清水平与随后的结直肠癌风险之间的关系，并研究JCV抗体水平的纵向变化作为结直肠癌后续发展的预测因子。我们假设JCV参与了结直肠癌发生的早期阶段，并且JCV的诊断前抗体将与随后结直肠癌和腺瘤性息肉的风险增加相关，特别是在抽血几年后确诊的病例中。最后，我们假设慢性活动性JCV感染的血清标志物，即在15年期间JCV抗体水平的上升，IgA血清阳性，Th2抗体谱(lgG4和gT；lgG1和3)，以及JCVT抗原的抗体将与随后的CRC/息肉的风险增加相关。我们提出的研究是创新的，因为它将纳入在结直肠癌/息肉诊断前几年测量的JCV感染的免疫标记物，包括六种不同的JCV蛋白抗体。华盛顿公司的队列是一个独特的环境，用来研究JCV感染在结直肠癌早期发展阶段中的作用，因为血液样本是在癌症诊断之前获取和储存长达30年的，而对于一个亚组个人，血液是在两个时间点采集的，相隔15年。这项研究的成本效益很高，因为将使用存档的样本。此外，研究结果将具有巨大的潜在公共卫生意义，因为JCV可能成为预防结直肠癌的新靶点，结直肠癌是人类第三常见的癌症。

DESCRIPTION (provided by applicant): JC virus (JCV), a common polyomavirus infection in humans, has been proposed as a potential risk factor for colorectal cancer. Several lines of laboratory evidence support a role for JCV in the early development of colorectal cancer. Unfortunately, there have been no epidemiologic studies of the association between past infection with JCV and colorectal cancer. We propose to conduct a matched case-control study of circulating prediagnostic antibodies to JCV and incident colorectal cancer nested within two community- based cohorts in Washington County, MD. The goal of this research is to characterize the relationship between infection with JC virus and colorectal cancer, so that future prevention strategies may be developed. Specifically, our aims are to measure prediagnostic serum antibody levels to JCV capsid and oncoproteins in 582 cases of colorectal cancer, 135 cases of pre-cancerous adenomatous polyps, and 1,299 matched controls, to determine the association between JCV antibody serostatus and subsequent colorectal cancer risk overall and across intervals of induction period, and to investigate longitudinal changes in JCV antibody levels as a predictor of subsequent colorectal cancer development. We hypothesize that JCV is involved in the early stages of colorectal carcinogenesis, and that prediagnostic antibodies to JCV will be associated with increased risk of subsequent colorectal cancer and adenomatous polyps, particularly among cases diagnosed several years after blood draw. Finally, we hypothesize that serologic markers of chronic active JCV infection, namely, a rise in JCV antibody levels over a 15-year period, IgA seropositivity, a Th2 antibody profile (lgG4>lgG1 and 3), and antibodies to JCVT-antigen will be associated with increased risk of subsequent CRC/polyps. Our proposed study is innovative in that it will incorporate immunologic markers of JCV infection measured years prior to colorectal cancer/polyp diagnosis, including six different antibodies to JCV proteins. The Washington Co. cohorts are a unique setting in which to investigate the role of JCV infection in early stages of colorectal cancer development, given that blood samples were obtained and stored up to 30 years prior to cancer diagnosis, and for a subset individuals, blood was obtained at two time points, 15 years apart. This study is highly cost-efficient, since archived samples will be used. Furthermore, study findings will be of great potential public health significance, as JCV could be a novel target for the prevention of colorectal cancer, the third most common cancer among humans.