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: 7781549
• 负责人: NICOLA J. CAMP
• 金额: $ 57.62万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7781549
• 关键词: Adult; B-Cell Lymphomas; B-Lymphocytes; Biopsy; Blood; Bone Marrow; Caucasians; Caucasoid Race; Cells; Chronic Lymphocytic Leukemia; Clinical Pathology; Collaborations; Complex; Computer software; Data; Development; Diagnosis; Disease; Distant; Elements; Epidemiologic Studies; Epidemiology; Etiology; Family; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Genetic Research; Genetic Risk; Genome; Genomic Segment; Genotype; Germ-Line Mutation; Haplotypes; Hematopoietic stem cells; Individual; International; Knowledge; Lead; Lymphoblastic Leukemia; Lymphoid Tissue; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Maps; Meiosis; Methods; Mining; Molecular Genetics; Multiple Myeloma; Nature; Other Genetics; Pathology; Play; Positioning Attribute; Predisposition; Public Health; Relative (related person); Research; Research Design; Research Personnel; Resources; Risk; Role; Sampling; Shapes; Single Nucleotide Polymorphism; Site; Small-Cell Lymphoma; Structure; Susceptibility Gene; Techniques; Translating; United States; Utah; Variant; adult leukemia; base; blood neoplasm; cancer genetics; case control; clinical decision-making; density; design; experience; genetic analysis; genetic epidemiology; genetic linkage analysis; genetic pedigree; genome-wide; genome-wide linkage; high risk; improved; infancy; innovation; insight; leukemia; lymph nodes; lymphoid neoplasm; member; novel; population based; public health relevance; working group

DESCRIPTION (provided by applicant): Chronic Lymphocytic Leukemia (CLL) is a B-cell lymphoproliferative disorder primarily involving the bone marrow, blood and lymph nodes. CLL is the most common type of leukemia in adults and although median survival can be quite long, between 8-12 years, most eventually succumb to their disease. The evidence for a genetic component to CLL is compelling but remains unknown, and is likely complex. However, opportunities to identify underlying variants are apparent -both by varied and unique study and analysis designs and via collaborative efforts. The research plan we propose is multifaceted, highly collaborative and includes several innovative techniques. We will pursue two study designs, each powerful to identify susceptibility genes with different underlying genetic models: high-risk pedigree-based shared genomic segment analysis and case- control association analyses. Genome-wide shared genomic segment analysis is a new method that requires extremely extended, high-risk pedigrees which are available only to researchers with genealogic resources, such as Utah. Our strategy for association will be both genome wide and candidate region. Ascertainment will involve two sites (Utah and Sheffield, UK) and will include both a discordant family-based element (Utah) and a population-based sample (UK). This approach exploits both the increased power of familial cases with the perspective of population-based samples. We are able to pursue these together due to software that we have developed. In addition to conventional analyses, we will develop new methods for the high-risk pedigree and case-control settings: homozygosity mapping in the high-risk pedigrees and case-control SGS and homozygosity mapping. Both conventional and novel methods will be performed as part of broader collaborative efforts. The resource that we will build is timely. CLL genetic research is still in its infancy. The concurrent development of these designs defines an extensive strategy for identifying regions of the genome harboring CLL susceptibility genes and will afford us the opportunity to play a significant role in shaping the direction of CLL genetic research. Particularly, Utah pedigrees, through their structure and high-risk nature, add a previously unrealized aspect to the global picture. If one design or collaborative effort can identify even a single susceptibility gene for CLL, we will have made an important and critical discovery in the etiology of CLL. Such a discovery would not only help our understanding of the etiology of CLL, but also may provide information about other lymphoproliferative disorders and may translate to other cancers. PUBLIC HEALTH RELEVANCE: This project is likely to lead to the identification of one or more genes predisposing to chronic lymphocytic leukemia (CLL). The individual public health implications are: the significantly increased accuracy that could be accomplished in risk estimation for CLL post-gene-identification and, in particular, identification of CLL precursors, insight into the overlapping genetic etiologies of CLL and other lymphoid neoplasms, and the potential improved ability for clinical decision making (for cases and gene carriers) based on genotype. The wider public health implications include the increased understanding that knowledge of any CLL predisposition gene will provide towards underlying the disease mechanism and direction towards the identification of additional predisposition genes.

描述（由申请人提供）：慢性淋巴细胞白血病（CLL）是一种主要累及骨髓、血液和淋巴结的 B 细胞淋巴增殖性疾病。 CLL 是成人中最常见的白血病类型，尽管中位生存期可能相当长（8 至 12 年），但大多数人最终死于该病。 CLL 的遗传因素的证据令人信服，但仍然未知，而且可能很复杂。然而，通过各种独特的研究和分析设计以及通过协作努力，识别潜在变异的机会是显而易见的。我们提出的研究计划是多方面的、高度协作的，并包括多种创新技术。我们将追求两种研究设计，每种设计都能够有效地识别具有不同潜在遗传模型的易感性基因：基于高风险谱系的共享基因组片段分析和病例对照关联分析。全基因组共享基因组片段分析是一种新方法，需要极其广泛的高风险谱系，而这些谱系只有拥有谱系资源的研究人员才能使用，例如犹他州。我们的关联策略将是全基因组范围和候选区域。确定将涉及两个地点（犹他州和英国谢菲尔德），并将包括不一致的基于家庭的元素（犹他州）和基于人口的样本（英国）。这种方法从基于人群的样本的角度利用了家族病例的增强力量。由于我们开发的软件，我们能够一起追求这些目标。除了常规分析之外，我们还将开发用于高风险谱系和病例对照设置的新方法：高风险谱系和病例对照 SGS 和纯合性映射中的纯合性映射。传统方法和新颖方法都将作为更广泛合作努力的一部分进行。我们将建立的资源是及时的。 CLL 基因研究仍处于起步阶段。这些设计的同时开发定义了一种广泛的策略，用于识别含有 CLL 易感基因的基因组区域，并使我们有机会在塑造 CLL 遗传研究方向方面发挥重要作用。特别是，犹他州的血统，通过其结构和高风险性质，为全球图景增添了以前未实现的一面。如果一项设计或协作努力能够识别 CLL 的单个易感基因，我们将在 CLL 的病因学方面取得重要且关键的发现。这样的发现不仅有助于我们了解 CLL 的病因，而且还可能提供有关其他淋巴增殖性疾病的信息，并可能转化为其他癌症。 公共健康相关性：该项目可能会导致识别一种或多种易患慢性淋巴细胞白血病 (CLL) 的基因。对个人公共卫生的影响是：可以显着提高 CLL 基因鉴定后风险评估的准确性，特别是 CLL 前体的鉴定，深入了解 CLL 和其他淋巴肿瘤的重叠遗传病因，以及基于基因型的临床决策（针对病例和基因携带者）的潜在改进能力。更广泛的公共卫生影响包括加深对任何 CLL 易感基因的了解，为疾病机制提供基础知识，并为识别其他易感基因提供方向。