Genetic susceptibility to acute lymphocytic and myeloid leukemia

 描述（由申请人提供）：急性淋巴细胞白血病（ALL）和急性髓细胞白血病（AML）是一种知之甚少且研究不足的疾病，具有高死亡率。虽然在ALL中发现的环境风险因素很少，但在最近的全基因组关联研究（GWAS）中已证实了儿童ALL的遗传易感性。然而，这些研究是在儿科患者中测试了有限数量的常见变异，留下了有关整个生命周期对ALL的遗传易感性以及常见和罕见变异的作用的未解问题。与ALL不同，针对AML易感性的生殖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的方式使用主要R 01（R 01 HL 102778 -04）生成的数据，从而对遗传学对ALL和AML易感性的贡献产生独特的见解。我们提出的研究有望通过对常见和较不常见的体质（遗传）遗传标记进行不可知论性询问来阐明白血病风险的途径。我们假设常见和罕见的生殖系遗传变异显著增加ALL和AML的几率。为了检验这些假设，我们将使用病例对照研究设计，利用我们的母研究R 01的现有数据，该研究产生了数千例接受异基因造血细胞移植（AlloHCT）治疗的充分表征的ALL和AML患者（病例）及其无关健康供体（对照）的高质量人口统计学、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）的易感性变异在较大的儿童和成人中显示出相同的关联。这是特别相关的，因为在已发表的GWAS中，ARID 5 B与ALL在不同年龄段的遗传变异强度变化的初步发现。此外，我们的研究人群具有独特的特征，可获得高分辨率HLA分型病例（alloHCT受体）和对照（匹配的非相关alloHCT供体），这将允许创新建模，包括匹配对分析，以更好地了解常见和罕见遗传变异，HLA类型和疾病的关系。HLA最近被认为与儿童ALL易感性有关，并被认为与AML有关。通过利用现有的大型GWAS，拟议的目标将有助于显著了解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。这些知识可能会导致这些致命癌症的早期检测，甚至预防的重大未来改进。

 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.