Genetic Epidemiology of Chronic Lymphocytic Leukemia

描述（由申请人提供）：慢性淋巴细胞白血病（CLL）是一种无法治愈的血液肿瘤，是美国高加索人最常见的b细胞恶性肿瘤之一。它对病因有很强的遗传贡献，是癌症中最高的家族性疾病风险之一。在初始资助期间，我们通过全基因组关联（GWA）研究和连锁研究对CLL的遗传病因学做出了重大贡献。我们在16q24.1染色体上的IRF8基因以及6p21.3染色体上的HLA区域内发现并确认了CLL的易感位点。我们还重复了之前的GWA发现，包括IRF4基因内的发现。我们的工作和其他人的一个显著特征是，几个GWA发现似乎在决定b细胞发育中起作用（例如，IRF4./IRF8）。此外，我们在HLA区域内的发现仅在家族性CLL病例的同质样本中观察到。在这个更新应用中，我们将我们的GWA发现带入下一步，进一步完善相关信号的位置，并扩展IRF4/IRF8的发现。具体而言，我们建议（Aim1）通过对IRF4/IRF8基因相关基因的遗传变异进行综合基因分型，来识别和验证CLL风险的新遗传变异。（目的2）通过靶向深度测序和在更大CLL病例和对照样本中的验证来表征我们位于染色体16q24.1上的IRF8区域。（目的3）在家族性CLL病例和对照的发现和验证样本中表征我们位于染色体6p21.3上的HLA区域。我们将利用我们独特的高风险CLL谱系持续资源来实现我们的目标，这些谱系是通过CLL遗传流行病学（GEC）联盟收集的。Slager和Caporaso，以及Mayo Clinic CLL病例对照研究，Mayo Clinic Biobank和InterLymph Consortium。我们提出的应用程序是GWA研究后合乎逻辑的下一步，并且根据我们的初步数据，它有很高的成功概率。我们拥有一支强大的多中心、多学科合作的研究团队，他们拥有综合的专业知识，能够成功地实现本提案的目标。在这个项目完成后，我们希望能发现其他影响CLL风险的新基因位点，这些基因位点是通过GWA研究无法确定的。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定位。总的来说，我们的研究结果将提供对CLL病理生物学的更好理解，并可能导致治疗CLL的新治疗方法，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.