Molecular Epidemiology of NHL and CLL

描述(由申请者提供)：非霍奇金淋巴瘤(NHL)目前在美国男性和女性中被诊断为第五种最常见的癌症。在NHL的病因学中，有几个候选易感基因的证据迅速积累，支持基于低外显性等位基因的多基因模型，符合共同变异、常见病假说。与此同时，在揭示癌症的环境风险因素方面也取得了很大进展，该领域正在走向成熟，开始评估基因与环境的相互作用。本申请是续订R01 CA92153的申请，以使我们能够继续调查这一重要癌症的病因。我们在最初赠款的科学和业务目标方面取得了重大进展。这次更新的目的是通过在上一次赠款周期的几个关键线索的基础上，增加我们对非霍奇金淋巴瘤遗传和环境病因学的理解。有四个具体目标：1)评估炎症和免疫基因的遗传变异性与NHL风险的关系；2)评估NHL的流行病学危险因素，重点是病史(包括阿司匹林和NSAID的使用、免疫史和他汀类药物的使用)、能量平衡(包括肥胖和体力活动)、饮食(包括抗氧化剂相关的营养素和类黄酮)以及农业/农药暴露(包括农场实践和接触苯氧乙酸、三嗪除草剂和有机磷杀虫剂)；3)评估NHL病因学中的基因-环境相互作用，重点是免疫相关基因与免疫疾病/条件的相互作用，以及参与致癌物质代谢和解毒途径的基因与抗氧化剂相关饮食因素的相互作用；以及4)验证InterLymph Consortium中选定的遗传和流行病学危险因素的发现，包括来自Aim 1的前20个单核苷酸多态(SNPs)。为了实现这些目标，我们将利用我们正在进行的基于临床的NHL病例对照研究。截至2007年4月，我们已经登记了940例非霍奇金淋巴瘤病例和1,197个控制措施，在完成这次续签申请时，我们估计将有2,000个非霍奇金淋巴瘤病例和2,000个控制措施。我们已经建立了一个优秀的资源，拥有专家血液病理学家的中心表型定义，广泛收集的生物样本和风险因素数据，获得最先进的生物信息学和基因分型，以及一支成熟的跨学科研究团队。在这次更新中，我们将有极好的能力来检验我们的先验假设，我们将使用两阶段设计来提高我们的基因研究的效率。我们通过为综合研究提供数据，以及在几项倡议中发挥领导作用，全面参与了InterLymph Consortium。该联盟的汇集活动对于在大的、独立的样本中复制至关重要，以便更快地推进该领域并充分解决与NHL亚型相关的假说。更新目标的完成将大大促进我们对这种癌症的病因的了解，并应有助于确定预防和控制NHL的新方法。公共卫生相关性：非霍奇金淋巴瘤(NHL)在美国是一种重要的癌症，我们对这种恶性肿瘤的遗传和环境风险因素只有部分了解。我们将在前一个资助期的基础上取得进展，完成我们的更新目标将大大促进我们对这种癌症的病因的了解，并应有助于确定预防和控制非霍奇金淋巴瘤的新方法。

DESCRIPTION (provided by applicant): Non-Hodgkin lymphoma (NHL) is now the 5th most frequently diagnosed cancer among both men and women in the US. There is rapidly accumulating evidence for several candidate susceptibility genes in the etiology of NHL, supporting a polygenic model based on low-penetrance alleles in line with the common-variant, common- disease hypothesis. In parallel, much progress has been made in uncovering environmental risk factors for this cancer, and the field is maturing to the point of beginning to evaluate gene-environment interactions. This application is a request for renewal of R01 CA92153 to allow us to continue our investigation into the etiology of this important cancer. We have made major progress on the scientific and operational goals from the original grant. The goal of this renewal is to increase our understanding of the genetic and environmental etiology of NHL by building on several key leads from the last grant cycle. There are four specific aims: 1) To evaluate the association of inherited variability in inflammation and immune genes with risk of NHL; 2) To evaluate epidemiologic risk factors for NHL, with a focus on medical history (including aspirin and NSAID use, immunization history, and statin use), energy balance (including obesity and physical activity), diet (including antioxidant-related nutrients and flavonoids), and farming/pesticide exposure (including farm practices and exposure to phenoxyacetic acid and triazine herbicides and organophosphate insecticides); 3) To evaluate gene-environment interactions in the etiology of NHL, with a focus on the interaction of immune-related genes with immunologic diseases/conditions and the interaction of genes involved in carcinogen metabolism and detoxification pathways with antioxidant-related dietary factors; and 4) To validate selected genetic and epidemiologic risk factor findings from this renewal in the InterLymph Consortium, including the top 20 single nucleotide polymorphisms (SNPs) from Aim 1. To achieve these aims, we will utilize our ongoing, clinic-based case-control study of NHL. Through April 2007, we have enrolled 940 NHL cases and 1,197 controls, and by the completion of this renewal application, we will have an estimated 2,000 NHL cases and 2,000 controls. We have built an outstanding resource, with central phenotypic definition by expert hematopathologists, extensive collection of biologic samples and risk factor data, access to state-of-the-art bioinformatics and genotyping, and an established, interdisciplinary study team. In this renewal, we will have excellent power to test our a priori hypotheses, and we will use a two-stage design for our genetic studies to increase efficiency. We are fully engaged in the InterLymph Consortium by contributing data for pooled studies, as well as taking leadership roles in several initiatives. The pooling activities of the consortium are critical for replication in large, independent samples, in order to more rapidly advance the field and to adequately address hypotheses related to NHL subtypes. Completion of the renewal aims will significantly advance our understanding of the etiology of this cancer, and should help identify new approaches for the prevention and control of NHL. PUBLIC HEALTH RELEVANCE: Non-Hodgkin lymphoma (NHL) is an important cancer in the United States, and we only partially understand the genetic and environmental risk factors for this malignancy. We will build off the progress from the previous funding period, and completion of our renewal aims will significantly advance our understanding of the etiology of this cancer, and should help identify new approaches for the prevention and control of NHL.