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: 7992446
• 负责人: NICOLA J. CAMP
• 金额: $ 53.71万
• 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 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992446
• 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; Health; 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; 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.

描述(申请人提供)：慢性淋巴细胞性白血病(CLL)是一种B细胞淋巴增生性疾病，主要累及骨髓、血液和淋巴结。慢性淋巴细胞性白血病是成人中最常见的白血病类型，虽然中位生存期可能相当长，在8-12年之间，但大多数人最终会死于他们的疾病。CLL的遗传成分的证据是令人信服的，但仍然未知，而且可能是复杂的。然而，识别潜在变异的机会是显而易见的--无论是通过各种独特的研究和分析设计，还是通过合作努力。我们提出的研究计划是多方面的，高度协作，并包括几项创新技术。我们将进行两个研究设计，每个设计都有效地识别具有不同潜在遗传模式的易感基因：基于高危家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的方法，它需要极其广泛的、高风险的家系，只有拥有家谱资源的研究人员才能获得，如犹他州。我们的联合战略将是全基因组和候选区域。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)。这种方法既利用了家族性病例增加的力量，又从以人口为基础的样本的角度出发。由于我们开发的软件，我们能够一起追求这些。除了常规分析外，我们还将为高危家系和病例对照环境开发新的方法：高危家系的纯合子作图和病例对照SGS和纯合子作图。传统方法和新方法都将作为更广泛的合作努力的一部分进行。我们将建立的资源是及时的。CLL基因研究仍处于初级阶段。这些设计的同时开发为识别含有CLL易感基因的基因组区域定义了一种广泛的策略，并将为我们提供机会在塑造CLL遗传学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，为全球图景增加了以前未意识到的方面。如果一个设计或合作努力能够识别出CLL的一个易感基因，我们将在CLL的病因学上取得一个重要和关键的发现。这样的发现不仅有助于我们了解CLL的病因，还可能提供有关其他淋巴增生性疾病的信息，并可能转化为其他癌症。