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: 7908712
• 负责人: Susan L Slager
• 金额: $ 64.03万
• 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/7908712
• 关键词: Affect; B-Lymphocytes; Blood; Bone Marrow; Cancer Biology; Caucasians; Caucasoid Race; Chromosome Mapping; Chromosomes; Chronic Lymphocytic Leukemia; Clinic; Clinical Pathology; Color; Consent; Data; Data Quality; Disease; Etiology; Family; Family history of; First Degree Relative; Flow Cytometry; Future; Genes; Genetic; Genetic Markers; Genetic Risk; Genome; Genomics; Genotype; Germ-Line Mutation; Hematopoietic Neoplasms; Hematopoietic stem cells; Individual; Institution; Life; Link; Location; Lymph Node Disorder; Lymphoid Tissue; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Maps; Molecular Genetics; Multiple Myeloma; Other Genetics; Patients; Positioning Attribute; Predisposition; Recruitment Activity; Relative (related person); Research; Research Personnel; Resources; Risk Factors; Siblings; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Stem cells; Susceptibility Gene; Testing; United States; adult leukemia; base; blood neoplasm; density; design; experience; family genetics; gene discovery; genetic epidemiology; genetic linkage analysis; genetic pedigree; high risk; insight; leukemia; multidisciplinary; programs; quality assurance; translational study

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）：本研究旨在最大限度地确定与慢性淋巴细胞白血病（CLL）（一种血癌）病因相关的基因。我们建议通过使用密集的遗传标记图谱对 200 个高危 CLL 家系进行基于家庭的研究来实现这一目标。由于没有任何一个机构能够收集如此多的谱系，因此只有通过合作才能绘制 CLL 易感基因图谱。因此，我们组建了一支由经验丰富的研究人员组成的多中心、多学科团队。通过我们的共同努力，我们的 CLL 遗传流行病学 (GEC) 联盟将发展成为一个以家庭为基础的基因发现研究资源，旨在识别和表征 CLL 的遗传风险。此外，鉴于其他血液和淋巴结疾病可能由共同的干细胞引起，通过该联盟鉴定的遗传信息可能会提供有关其他血液和淋巴结疾病的遗传学以及一般癌症易感性的重要见解。作为一个联盟，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。各招募中心的调查人员将对诊所的CLL患者进行筛查，以识别和确定那些有CLL家族史的患者。此外，具有 CLL 家族史的 CLL 患者将通过 CLL 研究联盟 (CRC) 进行识别，该联盟致力于为 CLL 患者识别和测试有前景的疗法。然后，已确定的具有 CLL 家族史的 CLL 患者的在世亲属将被招募到我们的研究中。生物样本和危险因素数据将从所有同意的受试者中获得。 （目标2）确定从目标1中确定的高风险CLL家族中选择的前兆CLL个体。我们将对目标1中确定的高风险CLL家族子集中的200名未受影响的CLL患者一级亲属进行四色流式细胞术。将使用新鲜血液，并由一个实验室进行所有流式细胞术测试，提供数据质量保证。收集到的信息将用于目标 3，以提高检测连锁的统计能力，并为未来的转化研究提供基础。 （目标 3）进行基因组筛选，以绘制增加 CLL 易感性的基因的染色体位置。使用分布在所有染色体上的高密度单核苷酸多态性面板，我们将对目标 1 中确定的高风险 CLL 谱系中的所有个体进行基因分型。然后，我们将进行连锁分析，以确定与 CLL 相关的染色体位置。我们的次要目标是精细绘制通过连锁分析确定的遗传区域。我们期望通过目标 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，我们将通过对区域内的其他标记进行基因分型来精细绘制这些区域。