Genetic Epidemiology of Chronic Lymphocytic Leukemia

描述(申请人提供)：慢性淋巴细胞白血病(CLL)是一种不可治愈的血液肿瘤，是美国高加索人最常见的B细胞恶性肿瘤之一。它在病因学上有很强的遗传贡献，是癌症中最高的家族疾病风险之一。在最初的资助期间，我们通过全基因组关联(GWA)研究和连锁研究，对慢性淋巴细胞性白血病的遗传病因学做出了重大贡献。我们已经在染色体16q24.1上的IRF8基因和染色体6p21.3上的HLA区发现并确认了CLL的易感基因。我们还复制了以前的GWA发现，包括IRF4基因中的那些。我们的工作和其他工作的一个显著特点是，GWA的几个发现似乎在决定B细胞发育方面起作用(例如，IRF4/IRF8)。此外，我们在人类白细胞抗原区域的发现只在我们的家族性CLL病例的同种样本中观察到。在这一更新申请中，我们将GWA的发现带到下一步，以进一步细化相关信号的位置，并在IRF4/IRF8发现的基础上进行扩展。具体地说，我们建议(Aim1)通过对与IRF4/IRF8基因相关的基因的遗传变异进行全面的基因分型来识别和验证CLL风险的新的遗传变异。(目的2)通过有针对性的深度测序和大量CLL病例和对照样本的验证，确定位于染色体16q24.1上的IRF8区域的特征。(目的3)在家族性慢性淋巴细胞性白血病患者和对照的发现和验证样本中，对位于染色体6p21.3的人类白细胞抗原区域进行特征分析。我们将利用我们独特的高危慢性淋巴细胞性白血病家系资源来实现我们的目标，这些家系是通过Slager博士和Caporaso博士领导的CLL(GEC)遗传流行病学联盟以及Mayo Clinic CLL病例对照研究、Mayo Clinic Biobank和InterLymph Consortium收集的。我们建议的应用是GWA研究之后合乎逻辑的下一步，根据我们的初步数据，它有很高的成功几率。我们拥有一支强大的协作、多中心、多学科的调查团队，他们拥有共同的专业知识，能够成功地实现这项提案的目标。在这个项目完成后，我们希望能够发现更多影响慢性淋巴细胞性白血病风险的新的基因座，而这些新的基因座是无法通过GWA研究确定的。我们还将对我们的GWA基因座进行更彻底的评估，以便进一步完善相关信号的位置。总而言之，我们的发现将有助于更好地了解CLL的病理生物学，并可能导致治疗CLL的新的治疗方法，并改善我们对CLL患者亲属的咨询。

DESCRIPTION (provided by applicant): Chronic lymphocytic leukemia (CLL) is an incurable neoplasm of the blood and is one of the most common B-cell malignancies in Caucasians in the United States. It has a strong genetic contribution to etiology, with one of the highest familial risks of disease among cancers. During the initial funding period, we have made substantial contributions to the genetic etiology of CLL through genome-wide association (GWA) studies and linkage studies. We have identified and confirmed susceptibility loci of CLL in the IRF8 gene on chromosome 16q24.1, as well as within the HLA region on chromosome 6p21.3. We also replicated previous GWA findings, including those within the IRF4 gene. One striking feature of our work and others is that several of the GWA findings appear to act in determining B-cell development (e.g., IRF4./IRF8). Further, our finding within the HLA region was only observed in our homogenous sample of familial CLL cases. In this renewal application, we take our GWA findings to the next step to further refine the location of the associated signals and to expand upon IRF4/IRF8 findings. Specifically, we propose to (Aim1) identify and validate new genetic variants of CLL risk by comprehensively genotyping genetic variants in genes related to IRF4/IRF8 genes. (Aim 2) to characterize our IRF8 region located on chromosome 16q24.1 through targeted deep sequencing and validation in larger sample of CLL cases and controls. (Aim 3) to characterize our HLA region located on chromosome 6p21.3 in discovery and validation samples of familial CLL cases and controls. We will carry-out our Aims using our unique ongoing resource of high-risk CLL pedigrees that are collected through the Genetic Epidemiology of CLL (GEC) Consortium led by Drs. Slager and Caporaso, as well as the Mayo Clinic CLL case-control study, Mayo Clinic Biobank, and the InterLymph Consortium. Our proposed application is the logical next step following a GWA study, and given our preliminary data, it has a high probability of success. We have a strong collaborative multicenter, multidisciplinary team of investigators who have the combined expertise to successfully carry out the Aims of this proposal. At the completion of this project, we expect to identify additional novel loci influencing CLL risk that could not have been identified through GWA studies. We will also provide a more thorough evaluation of our GWA loci in order to further refine the location of the associated signal. Collectively, our findings will provide for a better understanding of CLL pathobiology and may lead to novel therapeutic approaches to treating CLL and improve our counseling to relatives of CLL patients.