Molecular epidemiology of acute lymphoblastic leukemia in children with Down syndrome

修改后的项目摘要/摘要部分 唐氏综合征(DS)是急性淋巴细胞性白血病(ALL)的最强危险因素之一， 与没有DS的儿童相比，风险增加了20倍。DS-ALL儿童存活率保持在10%-20% 低于非DS-ALL患者，原因是复发和毒性。患有DS的儿童也有 增加了几种出生缺陷和慢性健康状况的风险。尽管这些增加的风险一直是 几十年来，人们一直知道白血病风险增加的基础仍然不清楚，而且有一个特别的 很少有研究探讨其他DS表型特征与ALL易感性之间的相互作用。而当 21号染色体基因剂量增加可能导致所有风险，仅有21三体是不够的， 因为DS儿童ALL的终生风险低于2%。我们假设额外的基因修饰物 与DS相关的其他表型结合21三体影响ALL的易感性。我们 到目前为止已经提出了几个重要的观察结果。1)在DS-ALL的第一个全基因组关联研究中， 我们观察到，所有易感基因(如CDKN2A、IKZF1)中的基因座对所有风险都有更强的影响 有DS的儿童与没有DS的儿童进行比较。2)我们有初步证据表明，患有DS-ALL的儿童 结构性出生缺陷的负担比没有ALL的DS儿童更大，也许这表明ALL- 有附加症状特征的易感表型。这些观察结果表明， 所有易感基因都在21三体背景下。然而，我们还没有系统地评估：1) 结构、罕见和21号染色体变异的作用，2)遗传遗传变异与 体细胞基因组异常，或3)其他DS相关表型在白血病易感性和 结果。通过NIH包容和儿童优先机制，我们和合作者发起了大型- 2500例DS儿童(~400例ALL)的规模基因组测序。利用这一前所未有的机会 基因组图谱和独特的DS队列，当前研究的目标是确定分子 DS儿童ALL的基础；并确定DS相关表型是否相关 具有ALL风险和/或结果(毒性、复发和存活)。为了实现这些目标，目标是 这项研究的目的是：1)全面分析与急性髓细胞白血病风险相关的可遗传变异 患有DS的儿童，重点关注结构、罕见和21号染色体变异；以及2)深入 DS-ALL儿童的表型分析以确定DS相关表型对白血病易感性的影响 和结果。这个项目将解决为什么患有DS的儿童的风险增加的根本问题 最重要的是，他们的白血病与没有DS的儿童有什么不同，以及其他与DS相关的表型可能有什么不同 影响所有的敏感性、存活率和毒性。这项研究的发现可能会导致基因的改善 针对DS儿童的测试和咨询策略。对驱动DS-ALL的基因的洞察可能会指导 开发靶向治疗。

Modified Project Summary/Abstract Section Down syndrome (DS) is one of the strongest risk factors for acute lymphoblastic leukemia (ALL), conferring a 20-fold increased risk compared to children without DS. Survival for children with DS-ALL remains 10-20% lower than that of non-DS-ALL patients, due to both relapse and toxicity. Children with DS also have an increased risk of several birth defects and chronic health conditions. Although these increased risks have been known for decades, the basis for the increased risk of leukemia remains unclear, and there is a particular paucity of studies exploring the interplay between other DS phenotypic features and ALL susceptibility. While increased dosage of chromosome 21 genes is likely contributory to ALL risk, trisomy 21 alone is not sufficient, as the lifetime risk of ALL in children with DS is under 2%. We hypothesize that additional genetic modifiers and other DS-related phenotypes in combination with trisomy 21 influence susceptibility to ALL. We have made several important observations to date. 1) In the first genome-wide association study of DS-ALL, we observed that loci in ALL susceptibility genes (e.g., CDKN2A, IKZF1) have stronger effects on ALL risk in children with DS compared to those without. 2) We have preliminary evidence that children with DS-ALL have a greater burden of structural birth defects than children with DS without ALL, perhaps suggesting an ALL- predisposition phenotype with additional syndromic features. These observations suggest unique patterns of ALL susceptibility in the background of trisomy 21. However, we have not yet systematically evaluated: 1) the role of structural, rare, and chromosome 21 variants, 2) the association between inherited genetic variation and somatic genomic abnormalities, or 3) the role of other DS-related phenotypes on leukemia susceptibility and outcomes. Through the NIH INCLUDE and Kids First mechanisms, we and collaborators have initiated large- scale genomic sequencing of 2,500 children with DS (~400 with ALL). Capitalizing on this unprecedented genomic profiling and unique DS cohort, the objectives of the current study are to determine the molecular underpinnings of ALL in children with DS; and to determine whether DS-related phenotypes are associated with risk of ALL and/or with outcomes (toxicities, relapse, and survival). To achieve these objectives, the aims of this study are to 1) perform a comprehensive analysis of heritable variation associated with risk of ALL in children with DS, with a focus on structural, rare, and chromosome 21 variants; and 2) conduct deep phenotyping of children with DS-ALL to identify the impact of DS-related phenotypes on leukemia susceptibility and outcomes. This project will address fundamental questions of why children with DS have an increased risk of ALL, how their leukemia differs from that of children without DS, and how other DS-related phenotypes may influence ALL susceptibility, survival, and toxicities. Findings from this study may lead to improved genetic testing and counseling strategies for children with DS. Insights into genes driving DS-ALL may guide development of targeted therapies.