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: 7909760
• 负责人: Susan L Slager
• 金额: $ 61.6万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7909760
• 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对200个高风险CLL谱系进行基于家庭的研究来做到这一点。由于没有一个机构能够收集这么多的谱系，因此绘制CLL的易感基因只有通过合作才能实现。因此，我们已经形成了一个多中心，多学科的团队经验丰富的调查员。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基于家庭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来自一个共同的干细胞，通过该联盟确定的遗传信息可能为其他血液和淋巴结疾病的遗传学以及一般的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）确定高危CLL家族进行遗传连锁分析。每个招募中心的研究人员将在临床筛选CLL患者，以确定和确定那些有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）进行鉴定，该联盟确定并测试有希望的CLL患者治疗方法。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。将从所有同意的受试者处获取生物标本和风险因素数据。（目的2）确定从目的1中确定的高危CLL家族中选择的CLL前体个体。我们将对来自Aim 1中确定的高风险CLL家族的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，一个实验室将执行所有流式细胞术测试，提供数据质量保证。收集到的信息将在Aim 3中使用，以增加检测关联的统计能力，并为未来的翻译研究提供基础。（目标3）进行基因组筛选，以确定增加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单核苷酸多态性的高密度面板，我们将对Aim 1中确定的高危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，以确定与CLL相关的染色体位置。我们的次要目标是通过连锁分析确定遗传区域的精细图谱。我们希望通过在Aim 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地绘制这些区域。