Genetic Epidemiology of Chronic Lymphocytic Leukemia

描述(由申请人提供)：这项研究旨在最大限度地确定导致慢性淋巴细胞白血病(CLL)的基因，这是一种血癌。我们建议通过使用密集的遗传标记图谱对200个高危慢性淋巴细胞性白血病家系进行研究来实现这一点。由于没有一家机构能够收集如此多的家系，绘制慢性淋巴细胞性白血病的易感基因图谱只能通过合作努力。因此，我们组建了一支由经验丰富的调查人员组成的多中心、多学科团队。通过我们的共同努力，我们的慢性淋巴细胞性白血病遗传流行病学(GEC)联盟将发展成为一个基于家庭的基因发现研究资源，将定位于识别和表征慢性淋巴细胞性白血病的遗传风险。此外，考虑到其他血液和淋巴结疾病可能源于共同的干细胞，通过该联盟确定的遗传信息可能为了解其他血液和淋巴结疾病的遗传学和一般癌症易感性提供重要的见解。作为一个联盟，我们的主要目标是(目标1)确定用于遗传连锁分析的高危慢性淋巴细胞性白血病家系。每个招募中心的调查人员将在诊所筛查CLL患者，以识别和确定那些有CLL家族病史的患者。此外，有CLL家族史的CLL患者将通过CLL研究联盟(CRC)进行识别，CRC是一个为CLL患者确定和测试有前景的治疗方法的联盟。有CLL家族病史的确诊的CLL患者的在世亲属将被招募到我们的研究中。将从所有同意的受试者那里获得生物检疫和风险因素数据。(目的2)确定从AIM 1确定的高危CLL家系中挑选的CLL前体个体。我们将对AIM 1确定的高危CLL家系中的200名未受影响的CLL患者的一级亲属进行四色流式细胞术。将使用新鲜血液，一个实验室将进行所有的流式细胞仪测试，提供数据质量保证。收集到的信息将用于目标3，以增加发现联系的统计能力，并将为今后的翻译研究提供基础。(目的3)进行基因组筛选，以定位增加CLL易感性的一个或多个基因的染色体位置。使用分布在所有染色体上的高密度单核苷酸多态组合，我们将对AIM 1中确认的高危CLL家系的所有个体进行基因分型。然后，我们将进行连锁分析，以确定被发现与CLL连锁的染色体位置。我们的次要目标是对通过连锁分析确定的遗传区域进行精细定位。我们希望通过目标3中进行的连锁分析确定至少一个重要的染色体区域。然后，我们将通过对区域内的其他标记进行基因分型来精细定位这些区域。

DESCRIPTION (provided by applicant): This study is designed to maximize the likelihood of identifying genes responsible for the etiology of Chronic Lymphocytic Leukemia (CLL), a blood cancer. We propose to do this through a family-based study of 200 high-risk CLL pedigrees using a dense map of genetic markers. Since no single institution is able to collect this many pedigrees, mapping susceptibility genes for CLL will only be possible through a collaborative effort. As such, we have formed a multicenter, multidisciplinary team of experienced investigators. Through our concerted effort, our Genetic Epidemiology of CLL (GEC) consortium will develop into a family-based gene-discovery research resource that will be positioned to identify and characterize genetic risk of CLL. Moreover, given that other blood and lymph node disorders may arise from a common stem cell, the genetic information identified through this Consortium may provide important insight about the genetics of other blood and lymph node disorders and about cancer susceptibility in general. As a Consortium, our primary aims are (Aim 1) to ascertain high-risk CLL families for genetic linkage analysis. Investigators from each recruitment center will screen CLL patients in the clinic to identify and ascertain those patients who have a family history of CLL. In addition, CLL patients with a family history of CLL will be identified through the CLL Research Consortium (CRC), a consortium that identifies and tests promising therapies for CLL patients. Living relatives of identified CLL patients with a family history of CLL will then be recruited into our study. Biospecimens and risk-factor data will be obtained from all consented subjects. (Aim 2) To ascertain precursor CLL individuals who are selected from the high-risk CLL families identified in Aim 1. We will conduct four-color flow cytometry on 200 unaffected first-degree relatives of CLL patients from a subset of the high-risk CLL families identified in Aim 1. Fresh blood will be used, and one lab will perform all flow cytometry tests, providing data quality assurance. The collected information will be used in Aim 3 to increase the statistical power to detect linkage and will also provide the basis for future translational studies. (Aim 3) To carry out a genomic screen to map the chromosomal location of the gene or genes that increase susceptibility to CLL. Using a high-density panel of single nucleotide polymorphisms that are distributed across all chromosomes, we will genotype all individuals from the high-risk CLL pedigrees identified in Aim 1. We then will perform linkage analyses to identify chromosomal locations that are found to be linked with CLL. Our Secondary Aim is to fine map genetic regions identified through linkage analysis. We expect to identify at least one significant chromosomal region through the linkage analysis conducted in Aim 3. We will then fine map these regions by genotyping additional markers within the regions.