Prediagnostic Markers of Immune Activation and Viral Infection and Risk of NHL

描述(申请人提供)：非霍奇金淋巴瘤(NHL)是美国第六大常见癌症。虽然在显性免疫抑制的情况下，发生NHL的风险大大增加，但绝大多数NHL，特别是B细胞性NHL，发生在似乎具有免疫能力的人身上。免疫功能正常人群中新发的B细胞性非霍奇金淋巴瘤的病因知之甚少。EB病毒(Epstein-Barr Virus，EBV)是一种嗜B细胞的伽玛疱疹病毒，与免疫抑制患者的NHL的病因有关，此类肿瘤通常具有可检测到的克隆性EBV DNA或基因产物。然而，在推测具有免疫能力的个体中，只有一小部分(约5%)的NHL是EBV基因组阳性的，并且大多数是非B细胞性NHL，因此EBV在这些个体的NHL的病因中所起的作用不太清楚。这项研究的总体目标是确定促进慢性B细胞刺激和/或导致控制不良的EB病毒(EBV)感染的免疫系统环境是否会导致B细胞NHL风险增加。慢性B细胞刺激会增加B细胞DNA修饰活动的发生，从而增加引发这些癌症的分子错误(癌基因易位或突变)的可能性。另一种可能促进这种遗传错误的机制是失去对EBV感染的免疫调节控制，因为EBV可以通过感染和转化B细胞促进淋巴肿大，以及通过上调诱导体细胞过度突变和随后的癌基因突变的分子的表达。这项研究的具体目的是：1)确定可能的B细胞激活指标，包括B细胞刺激细胞因子和/或与B细胞激活相关的分子水平升高，是否与明显免疫功能正常的人随后发生的B细胞NHL(弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤)有关；2)确定在B细胞非霍奇金淋巴瘤(DLBCL和滤泡性淋巴瘤)发生之前，是否出现与EBV重新激活一致的EBV抗体变化模式；以及3)确定这些生物标志物的变化与DLBCL和滤泡性淋巴瘤发展之间的时间关系。这些目标将在一项嵌套的病例对照研究(大约600例B细胞性非霍奇金淋巴瘤病例和600例匹配对照)中得到解决，该研究使用的是国防部血清库中存档的一系列诊断前血清样本。因此，这项研究将通过在诊断前对连续标本进行重复评估，为了解B细胞NHL发病关键时期的宿主和病毒因素提供一个窗口。我们的方法是在一系列样本中评估一系列与免疫和EBV相关的生物标记物，作为检测导致疾病的生物足迹的一种手段。这些研究将对免疫功能障碍和/或EBV感染失去免疫调节控制在B细胞非霍奇金淋巴瘤发生中的作用提供有价值的见解。

DESCRIPTION (provided by applicant): Non-Hodgkin lymphoma (NHL) is the sixth most common cancer in the United States. Although the risk of developing NHL is greatly elevated in the setting of overt immunosuppression, the great majority of NHL, and in particular B cell NHL, occur in individuals who appear to be immunocompetent. Relatively little is known about the etiology of the B cell NHL that arise de novo in immunocompetent populations. Epstein-Barr virus (EBV), a B cell-tropic gamma-herpesvirus, is clearly implicated in the etiology of NHL in immunosuppressed individuals, with such tumors often having detectable clonal EBV DNA or gene products. However, only a minority (approximately 5%) of the NHL seen in presumably immunocompetent individuals are EBV genome-positive, and most of these are non-B cell NHL, so the role of EBV in the etiology of NHL in such individuals is less clear. The overall goal of this study is to determine whether an immune system environment that promotes chronic B cell stimulation, and/or results in poorly-controlled Epstein-Barr virus (EBV) infection, will lead to an increased risk of B cell NHL. Chronic B cell stimulation can increase the occurrence of B cell DNA-modifying activities, thereby increasing the probability for the generation of molecular errors (translocations or mutations of oncogenes) that initiate these cancers. Another mechanism that could promote such genetic errors is loss of immunoregulatory control of EBV infection, as EBV can promote lymphomagenesis by the infection and transformation of B cells, as well as via the up-regulation of the expression of molecules that induce somatic hypermutation and subsequent oncogene mutation. The specific aims of this study are: 1) determine if indicators of likely B-cell activation, including elevated serum levels of B cell-stimulatory cytokines and/or of molecules that are associated with B cell activation, are associated with the subsequent development of B cell NHL (diffuse large B cell lymphoma [DLBCL] and follicular lymphoma) in apparently immunocompetent individuals; 2) determine whether altered patterns of antibodies to EBV, consistent with reactivation of EBV, are seen preceding the development of B cell NHL (DLBCL and follicular lymphoma), and 3) define the temporal relationship between changes in these biomarkers and the development of DLBCL and follicular lymphoma. These aims will be addressed in a nested case-control study (approximately 600 incident B cell NHL cases and 600 matched controls) using serial pre-diagnosis serum specimens archived in the Department of Defense Serum Repository. Therefore, this investigation will provide a window on host and viral factors during the critical period of B cell NHL pathogenesis by repeated assessment of sequential specimens prior to diagnosis. Our approach is to assess a range of immunity- and EBV-related biomarkers in serial specimens, as a means of detecting "bio- footprints" leading to disease. These studies should provide valuable insight on the role of immune dysfunction and/or loss of immunoregulatory control of EBV infection on the development of B cell NHL.