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: 7481077
• 负责人: Susan L Slager
• 金额: $ 62.3万
• 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/7481077
• 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; 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; 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; 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慢性淋巴细胞白血病（CLL）（一种血癌）病因学基因的可能性。我们建议通过使用密集的遗传标记图谱对200个高风险CLL家系进行以家族为基础的研究来实现这一点。由于没有一个单一的机构能够收集这么多的谱系，绘制慢性淋巴细胞白血病的易感基因只有通过合作才能实现。因此，我们组建了一个由经验丰富的研究者组成的多中心、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，将定位于识别和表征CLL的遗传风险。此外，考虑到其他血液和淋巴结疾病可能由共同的干细胞引起，通过该联盟确定的遗传信息可能提供关于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家庭的遗传连锁分析。来自每个招募中心的研究者将在诊所筛选CLL患者，以识别和确定具有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，该联盟确定并测试CLL患者的有希望的疗法。然后将具有CLL家族史的已确定的CLL患者的在世亲属招募到我们的研究中。将从所有知情同意的受试者中获取生物标本和风险因素数据。(Aim 2）确定从目标1中确定的高风险CLL家族中选出的CLL前体个体。我们将对200名CLL患者的未受影响的一级亲属进行四色流式细胞术，这些亲属来自目标1中确定的高风险CLL家族的一个子集。将使用新鲜血液，一个实验室将进行所有流式细胞术检测，提供数据质量保证。所收集的信息将用于目标3，以增加检测连锁的统计能力，并为未来的翻译研究提供基础。(Aim 3）进行基因组筛选以绘制增加对CLL的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单核苷酸多态性的高密度面板，我们将对来自目标1中鉴定的高风险CLL谱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。我们的第二个目标是通过连锁分析确定的遗传区域的精细地图。我们期望通过目标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，我们将通过对这些区域内的其他标记进行基因分型来精细绘制这些区域。