Genetic Epidemiology of Chronic Lymphocytic Leukemia

慢性淋巴细胞白血病的遗传流行病学

• 批准号: 7021850
• 负责人: Susan L Slager
• 金额: $ 67.36万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-23 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7021850
• 关键词: blood; clinical research; epidemiology; family; family genetics; genes; genetics

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.

描述（由申请人提供）：本研究旨在最大程度地识别负责慢性淋巴细胞性白血病（CLL）（血液癌）病因的基因的可能性。我们建议通过使用遗传标记的密集图对200个高风险CLL谱系的家庭研究来做到这一点。由于没有一个机构能够收集这么多的谱系，因此只能通过协作努力来映射CLL的易感基因。因此，我们组成了一个多中心，有经验的研究人员的多学科团队。通过我们的一致努力，我们对CLL（GEC）财团的遗传流行病学将发展为基于家庭的基因发现研究资源，该研究资源将定位，以识别和表征CLL的遗传风险。此外，鉴于其他血液和淋巴结疾病可能是由常见的干细胞引起的，因此通过该财团鉴定的遗传信息可能会提供有关其他血液和淋巴结疾病遗传学的重要见解，并且总体上对癌症的敏感性。作为一个财团，我们的主要目标是（目标1）确定高风险CLL家族以进行遗传连锁分析。每个招聘中心的研究人员将筛查诊所中CLL患者，以识别和确定那些具有CLL家族史的患者。此外，将通过CLL研究联盟（CRC）确定具有CLL家族史的CLL患者，该联盟鉴定并测试了CLL患者有希望的疗法。然后将招募具有CLL家族史的CLL患者的活着的亲属。将从所有同意受试者中获取生物测量和风险因素数据。 （AIM 2）确定从AIM 1中确定的高风险CLL家族中选择的前体CLL个体。我们将对来自AIM 1中确定的高风险CLL家族的200个不受影响的CLL患者的四色流式细胞仪进行。收集的信息将用于AIM 3，以增加检测联系的统计能力，并为将来的翻译研究提供基础。 （AIM 3）进行基因组筛选，以绘制增加基因的染色体位置或增加对CLL敏感性的基因。使用分布在所有染色体上的高密度单核苷酸多态性，我们将基因型在AIM 1中鉴定出的高风险CLL谱系的所有个体。然后，我们将执行连接分析以识别发现与CLL链接的染色体位置。我们的次要目的是通过连锁分析识别出详细的地图遗传区域。我们希望通过在AIM 3中进行的连锁分析来识别至少一个重要的染色体区域。然后，我们将通过在该区域内的其他标记进行基因分型来详细绘制这些区域。