Genetic susceptibility to acute lymphocytic and myeloid leukemia

 描述(申请人提供)：急性淋巴细胞性白血病(ALL)和急性髓系白血病(AML)是一种死亡率很高的疾病，人们对它们的认识和研究还不够深入。虽然几乎没有发现环境危险因素，但在最近的全基因组关联研究(GWAS)中已证实儿童ALL的遗传易感性。然而，这些研究是在儿科患者中测试有限数量的常见变异，留下了关于ALL在整个一生中的遗传易感性以及常见和罕见变异的作用的悬而未决的问题。与ALL不同的是，专注于AML易感性的种系遗传变异研究尚未发表。我们的方法、研究人群和疾病焦点允许以创新的方式使用初级R01(R01 HL102778-04)产生的数据，导致对遗传学对ALL和AML易感性的贡献的独特见解。我们拟议的研究有望通过不可知地询问常见和不常见的体质(遗传)遗传标记来阐明白血病风险的途径。我们假设，常见和罕见的生殖系遗传变异显著增加了ALL和AML的发病几率。为了验证这些假设，我们将使用病例对照研究设计，利用来自我们母公司R01研究的现有数据，该研究产生了高质量的人口学、人类白细胞抗原(HLA)和全基因组数据，这些数据涉及数千名接受异基因造血细胞移植(AllHCT)治疗的特征良好的ALL和AML患者(病例)及其无关的健康捐赠者(对照)。我们的研究人群包括儿科和成人所有病例，这使我们能够更好地了解所有与年龄相关的遗传效应，例如，幼儿(&lt；10岁)的易感变异是否显示出与年龄较大的儿童和成年人相同的关联。这是特别相关的，因为在已发表的GWA中，ARID5B基因变异强度随着年龄的变化而发生变化的初步发现。此外，我们的研究人群有一个独特的特点，即可获得高分辨率的HLA型病例(异基因血细胞移植受者)和对照(匹配的无血缘关系的异基因血细胞移植捐赠者)，这将允许创新建模，包括配对分析，以更好地理解常见和罕见的基因变异、人类白细胞抗原类型和疾病的关系。最近，人类白细胞抗原(HL A)被认为与儿童ALL易感性有关，并被推测为AML。通过利用现有的大量全球遗传资源，拟议的目标将有助于深入了解急性淋巴细胞白血病和急性髓细胞白血病风险的共同和罕见的遗传基础，以及急性淋巴细胞白血病和急性髓细胞白血病中与年龄有关的遗传联系。这一知识可能会在未来对这些致命癌症的早期检测和预防方面带来重大改进。

 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.