Genetic susceptibility to acute lymphocytic and myeloid leukemia

急性淋巴细胞白血病和粒细胞白血病的遗传易感性

• 批准号: 8896099
• 负责人: THERESA E HAHN
• 金额: $ 8.78万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896099
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute leukemia; Adult; Adult Acute Lymphocytic Leukemia; Adult Acute Myeloblastic Leukemia; Affect; Age; Allogenic; Benzene; Candidate Disease Gene; Case-Control Studies; Cause of Death; Cell Transplants; Cessation of life; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Childhood Acute Myeloid Leukemia; Constitutional; Data; Detection; Development; Diagnosis; Disasters; Disease; Early Diagnosis; Environmental Risk Factor; Etiology; Evaluation; Exposure to; Future; General Population; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genetic study; Genotype; Germ Lines; Grant; HLA Antigens; Hematologic Neoplasms; Hematopoietic; Heritability; Individual; Inherited; Ionizing radiation; Knowledge; Lead; Left; Longevity; Malignant Neoplasms; Marrow; Matched-Pair Analysis; Measures; Modeling; Myeloid Leukemia; Newly Diagnosed; Nuclear; Obesity; Occupational Exposure; Outcome; Parents; Pathway interactions; Patients; Population; Population Study; Predisposition; Prevention; Publishing; Radiation; Research; Research Design; Resolution; Resources; Risk; Risk Factors; Role; Smoking; Survival Analysis; Susceptibility Gene; Testing; Variant; age related; base; case control; chemotherapy; clinically relevant; cost effective; genetic association; genetic variant; genome wide association study; genome-wide; hematopoietic cell transplantation; human leukocyte antigen testing; innovation; insight; leukemia; mortality; outcome forecast; pediatric patients; population based; prenatal; programs; public health relevance; rare variant; research study; screening; validation studies

 DESCRIPTION (provided by applicant): Acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML) are poorly understood and under- studied diseases with high mortality rates. While few environmental risk factors have been identified in ALL, genetic susceptibility to pediatric ALL has been confirmed in recent genome wide association studies (GWAS). However, these studies were performed testing a limited number of common variants in pediatric patients, leaving unanswered questions about genetic susceptibility to ALL across the life span, as well as the role of common and rare variation. Unlike ALL, germ-line genetic variation studies focused on AML susceptibility have not been published. Our approach, study population and disease focus allow the data generated from the primary R01 (R01 HL102778-04) to be used in an innovative manner, leading to unique insights into the contribution of genetics to ALL and AML susceptibility. Our proposed research is expected to elucidate pathways for leukemia risk by agnostically interrogating both common and less common constitutional (inherited) genetic markers. We hypothesize that common and rare germ-line genetic variation significantly contributes to increased odds of ALL and AML. To test these hypotheses, we will use a case control study design leveraging existing data from our parent R01 study which produced high quality demographic, human leukocyte antigen (HLA) and genome-wide data on thousands of well-characterized ALL and AML patients (cases) treated with an allogeneic hematopoietic cell transplant (AlloHCT) and their unrelated healthy donors (controls). Our study population consists of both pediatric and adult ALL cases which allows us to gain greater understanding of age-associated genetic effects in ALL, e.g., do susceptibility variants in young children (<10 years) show the same association in older children and adults. This is particularly relevant due to the preliminary findings of changes in strength of genetic variants in ARID5B with ALL across age in published GWAS. In addition, our study population has a unique feature with the availability of high resolution HLA-typed cases (alloHCT recipients) and controls (matched unrelated alloHCT donors), which will allow innovative modeling, including matched pair analyses, to yield a greater understanding of the relationship of common and rare genetic variation, HLA type and disease. HLA have recently been implicated in pediatric ALL susceptibility and postulated for AML. By leveraging a large existing GWAS, the proposed aims will contribute to significant understanding of the common and rare genetic basis of ALL and AML risk, as well as age related genetic associations in ALL and AML. This knowledge could lead to significant future improvements in earlier detection, and perhaps prevention, of these deadly cancers.

 描述（由申请人提供）： 急性淋巴细胞白血病（ALL）和急性髓系白血病（AML）是人们对疾病知之甚少且研究不足的高死亡率疾病。虽然 ALL 中几乎没有发现环境危险因素，但最近的全基因组关联研究 (GWAS) 已证实儿科 ALL 的遗传易感性。然而，这些研究在儿科患者中测试了有限数量的常见变异，从而留下了关于整个生命周期对 ALL 的遗传易感性以及常见和罕见变异的作用的未解答的问题。与 ALL 不同，针对 AML 易感性的种系遗传变异研究尚未发表。我们的方法、研究人群和疾病重点允许以创新方式使用从主要 R01 (R01 HL102778-04) 生成的数据，从而对遗传学对 ALL 和 AML 易感性的影响产生独特的见解。我们提出的研究预计将通过不可知论地询问常见和不太常见的体质（遗传）遗传标记来阐明白血病风险的途径。我们假设常见和罕见的种系遗传变异会显着增加 ALL 和 AML 的发病率。为了检验这些假设，我们将使用病例对照研究设计，利用我们母公司 R01 研究的现有数据，该研究针对数千名接受同种异体造血细胞移植 (AlloHCT) 治疗的明确特征的 ALL 和 AML 患者（病例）及其无关的健康供体（对照）生成了高质量的人口统计、人类白细胞抗原 (HLA) 和全基因组数据。我们的研究人群包括儿童和成人 ALL 病例，这使我们能够更好地了解 ALL 中与年龄相关的遗传效应，例如，幼儿（<10 岁）的易感性变异在年龄较大的儿童和成人中是否显示出相同的关联。这是特别相关的，因为在已发表的 GWAS 中初步发现了 ARID5B 与 ALL 的遗传变异强度随年龄变化的变化。此外，我们的研究人群具有一个独特的特征，即可以获得高分辨率 HLA 型病例（alloHCT 受者）和对照（匹配的无关 alloHCT 供者），这将允许创新模型（包括配对分析）更好地了解常见和罕见遗传变异、HLA 类型和疾病的关系。最近有人认为 HLA 与儿童 ALL 易感性有关，并推测其与 AML 有关。通过利用现有的大型 GWAS，拟议的目标将有助于深入了解 ALL 和 AML 风险的常见和罕见遗传基础，以及 ALL 和 AML 中与年龄相关的遗传关联。这些知识可能会在未来对这些致命癌症的早期检测甚至预防方面带来重大改进。