Molecular Epidemiology of NHL and CLL

描述（由申请人提供）：非霍奇金淋巴瘤（NHL）的发病率和死亡率在过去50年中迅速增加，这些趋势在很大程度上无法解释。慢性淋巴细胞性白血病（CLL）是西方世界最常见的白血病，并且似乎与小淋巴细胞性NHL具有生物学相关性。世界上最高的发病率和死亡率发生在美国中西部地区。在这项研究中，我们建议系统地测试假设，病史，农药/农业暴露，饮食和早期生活的因素，已提出了由最近的研究作为NHL或CLL的病因学是重要的。我们还将检验新的假设，即参与免疫功能和调节的具有功能性、常见变异多态性的基因与NHL或CLL的风险相关;这些基因包括编码炎症和调节细胞因子的基因（IL-1A、IL-1B、IL-1 RN、TNF α、Th 1/Th 2细胞因子（LTA、INF γ、IL-4、IL-4 RA、IL-6、IL-10、IL-13）和趋化因子（IL-8、SDF-1、CCR 2、CCR 5）。我们还将评估测量的环境因素可能改变或混淆这些候选基因与NHL和CLL风险之间的任何观察到的关联的程度。此外，在二次分析中，我们将评估基因-基因（通路内和通路间）以及选定的基因-环境相互作用。我们也将开始讨论NHL最常见亚型的病因异质性问题。为了验证这些假设，我们提出了一个基于临床的病例对照研究。我们将入组在马约诊所诊断的NHL（N=914）和CLL（N=238）的事件病例，这些病例在诊断时是明尼苏达州、爱荷华州或威斯康星州的居民，持续4.7年。所有病例将由一名血液病理学家进行审查，并分类到WHO分类系统中，冷冻和石蜡组织将被储存。病例将与1,152例基于临床的对照进行比较，这些对照的频率与年龄、性别和居住县相匹配。参与者将完成结构化的自我管理问卷，并提供DNA和血清的血液样本。通常有很好的统计能力来检验感兴趣的先验假设。我们已经为这项研究组建了一个跨学科的研究团队，这项研究将创造一个优秀的研究资源。总之，我们将评估关于NHL和CLL的环境和遗传风险因素的关键假设，并应大大有助于我们理解这些癌症的原因和可能的预防。

DESCRIPTION (provided by applicant): Non-Hodgkin Lymphoma (NHL) incidence and mortality have been rapidly increasing over the past 50 years, and these trends are largely unexplained. Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world, and appears to be biologically related to small lymphocytic NHL. Some of the highest incidence and mortality rates in the world occur in the upper midwestern United States. In this study, we propose to systematically test hypotheses regarding medical history, pesticide/farming exposures, diet and early life factors that have been raised by recent research as being important in the etiology of NHL or CLL. We will also test novel hypotheses that genes with functional, common variant polymorphisms involved in immune function and regulation are associated with risk of NHL or CLL; these include genes encoding inflammatory and regulatory cytokines (IL-1A, IL-1B, IL-1RN, TNFalpha, Thl/Th2 cytokines (LTA, INFgamma, IL-4, IL- 4RA, IL-6, IL-IO, IL-13), and chemokines (IL-8, SDF-1, CCR2, CCR5). We will also evaluate the extent that measured environmental factors might modify or confound any observed association between these candidate genes and risk of NHL and CLL. Furthermore, in secondary analyses, we will evaluate gene-gene (within and between pathways), as well as selected gene-environment interactions. We will also begin to address the issue of etiologic heterogeneity for the most common subtypes of NHL. To test these hypotheses, we propose a clinic-based case-control study. We will enroll incident cases of NHL (N=914) and CLL (N=238) diagnosed at the Mayo Clinic over a 4.7-year time period who are residents of Minnesota, Iowa or Wisconsin at the time of diagnosis. All cases will be reviewed by a single hematopathologist and classified into the WHO classification system, and frozen and paraffin tissue will be banked. Cases will be compared to 1,152 clinic-based controls frequency matched on age, sex, and county of residence. Participants will complete structured self-administered questionnaires and provide a blood sample for DNA and serum. There is generally excellent statistical power to test the a priori hypotheses of interest. We have assembled an interdisciplinary research team for this study, and this study will create an outstanding research resource. In summary, we will evaluate critical hypotheses regarding environmental and genetic risk factors for NHL and CLL, and should greatly contribute to our understanding the causes and possible prevention of these cancers.