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年中迅速上升，这些趋势在很大程度上是无法解释的。慢性淋巴细胞性白血病(CLL)是西方世界最常见的白血病，与小淋巴细胞性非霍奇金淋巴瘤有生物学关系。世界上一些发病率和死亡率最高的地区发生在美国中西部上段。在这项研究中，我们建议系统地检验关于病史、农药/农业暴露、饮食和早期生活因素的假说，这些假说在最近的研究中被认为是NHL或CLL的病因学中的重要因素。我们还将测试新的假设，即参与免疫功能和调节的具有功能性、常见变异的基因与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(IL-1A、IL-1B、IL-1RN、TNFpha、Th1/Th2细胞因子(LTA、INFGamma、IL-4、IL-4RA、IL-6、IL-IO、IL-13)和趋化因子(IL-8、SDF-1、CCR2、CCR5)的基因。我们还将评估测量的环境因素可能在多大程度上改变或混淆这些候选基因与NHL和CLL风险之间的任何已观察到的关联。此外，在二次分析中，我们将评估基因-基因(在途径内和途径之间)，以及选定的基因-环境相互作用。我们还将开始解决最常见的NHL亚型的病原学异质性问题。为了验证这些假设，我们提出了一项基于临床的病例对照研究。我们将登记梅奥诊所在4.7年期间诊断为明尼苏达州、爱荷华州或威斯康星州居民的NHL(N=914)和CLL(N=238)病例。所有病例都将由一名血液病理学家进行审查，并归入世卫组织分类系统，并将储存冰冻和石蜡组织。病例将与在年龄、性别和居住县相匹配的1152名以诊所为基础的对照进行比较。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出色的研究资源。综上所述，我们将评估有关非霍奇金淋巴瘤和慢性淋巴细胞性白血病的环境和遗传风险因素的关键假设，并将对我们理解这些癌症的原因和可能的预防做出很大贡献。

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.