Genetic Susceptibility to non-Hodgkin Lymphoma

描述(申请人提供)：非霍奇金淋巴瘤的遗传易感性-更新：全球非霍奇金淋巴瘤(NHL)发病率的急剧上升促使人们做出相当大的努力，以确定可能有助于预防和治疗这种疾病的因素，并进一步了解引发和维持淋巴系统恶性肿瘤的生物学机制。作为R01 CA 104682-01资助的延续，这项提案的总体目标是利用旧金山湾区两项大型病例对照研究的DNA识别与非霍奇金淋巴瘤风险有因果关系的基因变异：SF湾区NHL1(400例，800例对照)和SF湾区NHL2(1,800例，1,800对照)。到目前为止，我们在多项研究中识别非霍奇金淋巴瘤的遗传危险因素方面做出了相当大的贡献。在之前的资助期间，我们通过最近的基因组扫描和国际非霍奇金淋巴瘤流行病学研究(InterLymph)研究人员联盟的合作，确定了近30个与NHL密切相关的基因。这些基因存在于肥胖、炎症、荷尔蒙产生和先天免疫途径中。现在，使用Illumina基因分型平台，在Aim#1下，我们将对这些基因进行精细定位，以识别真正的NHL风险等位基因。在AIM#2下，作为正在进行的InterLymph内复制研究的一部分，我们将在Skibola博士带头进行的大型集合遗传研究的基础上，领导与NHL相关的基因的精细定位。利用最近基因组扫描的数据，在AIM#3中，我们将评估拷贝数变化对NHL风险的影响，这将在我们其他的NHL病例和对照中得到证实。最后，我们将测试通过AIMS 1和2确定的推定原因多态的功能，并对危险等位基因进行机制研究，以获得进一步的见解，这将增强我们目前对淋巴肿大机制的理解。这些研究的结果1)可转化为旨在减轻全球非霍奇金淋巴瘤公共健康负担的预防和治疗计划；2)使用已有的两项非霍奇金淋巴瘤病例对照研究的DNA；3)使用我们基因组扫描中已有的数据；4)将首次根据人口研究中的拷贝数变化报告非霍奇金淋巴瘤的遗传易感性；5)将支持在InterLymph联盟内进行复制、精细绘图和汇集分析的主要努力。公共卫生意义：2008年，非霍奇金淋巴瘤(NHL)将导致美国超过63,000例新诊断病例和20,000例相关死亡病例，以及全球超过30,000例病例和172,000例死亡病例。在过去的几十年里，NHL的发病率和死亡率稳步上升，使其成为美国第五大最常见的癌症。家族遗传学在导致淋巴瘤方面发挥了重要作用，常见的基因变异可能会影响疾病的易感性。这些研究将利用遗传学来增加我们对淋巴瘤在体内如何发展的了解，并提供有关环境因素和生活方式暴露的线索，这些因素和生活方式暴露可能会导致疾病风险，这些线索可能转化为NHL筛查、预防和治疗计划。

DESCRIPTION (provided by applicant): Genetic Susceptibility to Non-Hodgkin Lymphoma - Renewal: Dramatic increases worldwide in the incidence of non-Hodgkin lymphoma (NHL) have stimulated considerable efforts to identify factors that may aid in the prevention and treatment of this disease and to further our understanding of the biological mechanisms that initiate and sustain a lymphoid malignancy. As a continuation of grant R01 CA 104682-01, the overall goal of this proposal is to identify genetic variants that are causally related to risk of NHL using DNA from two large case-control studies based in the San Francisco Bay Area: SF Bay Area NHL1 (400 cases, 800 controls) and SF Bay Area NHL2 (1,800 cases, 1,800 controls). We have made considerable contributions to the field to date in identifying genetic risk factors of NHL in multiple studies. We have identified nearly thirty genes strongly associated with NHL during the previous grant period, from a recent genome scan and through collaborations within the International Consortium of Investigators Working on NHL Epidemiologic Studies (InterLymph). These genes lie in the obesity, inflammation, hormone production and innate immunity pathways. Now, using the Illumina genotyping platform, under Aim#1, we will fine map these genes to identify true NHL risk alleles. Under Aim#2, as part of ongoing replication studies within InterLymph, we will lead the fine mapping of genes associated with NHL based on a large pooled genetic study currently underway that is being spearheaded by Dr. Skibola. Using data from a recent genome scan, in Aim#3, we will assess the influence of copy number variation on risk of NHL, which will then be confirmed in our additional NHL cases and controls. Finally, we will test the function of putatively causal polymorphisms identified through Aims 1 and 2 and perform mechanistic studies of risk alleles to gain further insights that will enhance our current understanding of mechanisms involved in lymphomagenesis. Results from these studies 1) can be translated into prevention and treatment programs aimed at reducing the public health burden of NHL worldwide; 2) use already existing DNA from two NHL case-control studies; 3) use already existing data from our genome scan; 4) will be the first to report genetic susceptibility of NHL based on copy number variation in population studies; and 5) will support major efforts to perform replication, fine mapping and pooled analyses within the InterLymph consortium. PUBLIC HEALTH RELEVANCE: In 2008, non-Hodgkin lymphoma (NHL) will account for over 63,000 newly diagnosed cases and 20,000 associated deaths in the U.S. and over 300,000 cases and 172,000 deaths worldwide. Incidence and mortality rates have steadily increased over the last several decades, making NHL the fifth most common cancer in the U.S. An important role for family genetics has been established in causing lymphoma and common genetic variants may influence disease susceptibility. These studies will use genetics to increase our understanding of how lymphoma develops in the body and provide clues about environmental agents and lifestyle exposures that contribute to disease risk that may be translated to NHL screening, prevention and treatment programs.