Genetic determinants of lymphocyte traits and risk of acute lymphoblastic leukemia in children with Down syndrome

唐氏综合症儿童淋巴细胞特征和急性淋巴细胞白血病风险的遗传决定因素

• 批准号: 10700064
• 负责人: Adam De Smith
• 金额: $ 12.38万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10700064
• 关键词: Acute Lymphocytic Leukemia; Address; Blood Cells; CDKN2A gene; Child; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Chromosome 21; Chronic; Clinical; Congenital Heart Defects; Data; Development; Down Syndrome; Early Intervention; Etiology; Face; Future; GATA3 gene; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genomics; Health; Hematopoiesis; Individual; Inferior; Intervention; Lymphocyte; Lymphocyte Count; Malignant Childhood Neoplasm; Measures; Mendelian randomization; Modeling; Outcome; Patient-Focused Outcomes; Patients; Penetrance; Performance; Polymorphism Analysis; Predictive Value; Predisposition; Prevention approach; Production; Relative Risks; Risk; Risk Factors; Role; Sampling; Single Nucleotide Polymorphism; Tail; Testing; Toxic effect; Treatment-related toxicity; Trisomy; Tumor Subtype; United States National Institutes of Health; Variant; adverse outcome; cell type; data portal; database of Genotypes and Phenotypes; genetic testing; genetic variant; genome sequencing; genome wide association study; genome-wide analysis; high risk; individualized prevention; instrument; leukemia; novel; polygenic risk score; predictive modeling; prevent; preventive intervention; programs; relapse risk; risk variant; statistics; trait; treatment risk; tumor; whole genome

ABSTRACT Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and children with Down syndrome (DS) have an up to 30-fold increased risk of developing ALL (DS-ALL). DS-ALL patients also have increased treatment-related toxicities, increased risk of relapse, and worse overall survival than ALL patients without DS. Prevention or early intervention of DS-ALL will require prediction models incorporating genetic risk; however, little is known regarding genetic risk of DS-ALL beyond the constitutive trisomy of chromosome 21. We will leverage the extreme susceptibility of DS to discover risk factors for DS-ALL. In a recent two-sample Mendelian randomization (MR) analysis of blood cell traits and ALL in children without DS, we found that a genetic propensity for overproduction of lymphocytes, overall and in relation to other blood cell types, was causally associated with an increased risk of ALL. Building on this finding, and given our recent demonstration that ALL-associated genetic risk variants appear to confer larger effects in children with DS, we will perform the first comprehensive study of the role of blood cell trait genetic variation in risk of DS-ALL, and we will also assess potential associations with particular tumor alterations and patient clinical outcomes. These analyses will be conducted using whole-genome sequencing (WGS) data from at least 413 DS-ALL cases and over 1500 DS controls, generated through the Gabriella Miller Kids First and NIH INCLUDE Programs and which will be publicly available through dbGaP and the Kids First Data Portal. In Aim 1, we will use the germline WGS data to perform a GWAS of DS-ALL, and then use summary statistics from this GWAS to perform a two-sample MR analysis of blood cell traits and DS-ALL risk, using genetic instruments already developed in our recent MR study of non- DS ALL. We will next construct polygenic risk scores (PRS) for each blood cell trait and examine the risk of DS- ALL at the tails of PRS distributions, as well as evaluating the predictive performance of each PRS model for DS-ALL risk using goodness-of-fit measures. We will also test whether single nucleotide polymorphisms (SNPs) previously associated with lymphocyte traits may also be associated with DS-ALL risk. In Aim 2, we will investigate the association between blood cell trait genetic variation and somatic features and clinical outcomes in DS-ALL patients. First, we will assess whether there may be tumor subtype-specific associations in the MR analysis, PRS, and candidate SNPs identified in Aim 1, with a focus on the prevalent CRLF2-rearrangements and IKZF1 deletions in DS-ALL. Next, in a case-only analysis we will explore whether PRS for blood cell traits may show association with DS-ALL patient clinical outcomes, including treatment-related toxicity, risk of relapse, and overall survival. This study will shed light on the etiology of DS-ALL, and reveal novel risk factors that may guide genetic testing and inform future precision prevention approaches through identification of children with DS with the greatest risk of ALL, as well as potentially those DS-ALL patients with high risk of adverse outcomes.

摘要 急性淋巴细胞白血病（ALL）是最常见的儿童恶性肿瘤， 综合征（DS）患者发生ALL（DS-ALL）风险增加30倍。DS-ALL患者还具有 与ALL患者相比，治疗相关毒性增加，复发风险增加，总生存期更差 没有DS DS-ALL的预防或早期干预需要纳入遗传风险的预测模型; 然而，除了21号染色体的组成性三体之外，关于DS-ALL的遗传风险知之甚少。我们 将利用DS的极端易感性来发现DS-ALL的风险因素。在最近的两个样本中， 对无DS儿童的血细胞性状和ALL进行孟德尔随机化（MR）分析，我们发现， 淋巴细胞过度产生的遗传倾向，总体上和与其他血细胞类型相关， 与ALL风险增加有因果关系。基于这一发现，鉴于我们最近的演示， ALL相关的遗传风险变异似乎对DS儿童产生更大的影响，我们将进行 首次全面研究血细胞性状遗传变异在DS-ALL风险中的作用，我们还将评估 与特定肿瘤改变和患者临床结果的潜在关联。这些分析将 使用来自至少413例DS-ALL病例和超过1500例DS的全基因组测序（WGS）数据进行 控制，通过加布里埃拉米勒儿童第一和国家卫生研究院纳入计划，这将是公开的 通过dbGaP和Kids First Data Portal提供。在目标1中，我们将使用生殖系WGS数据来执行 DS-ALL的GWAS，然后使用该GWAS的汇总统计量进行双样本MR分析， 血细胞性状和DS-ALL风险，使用我们最近对非- DS ALL。接下来，我们将为每个血细胞性状构建多基因风险评分（PRS），并检查DS的风险- 所有在PRS分布的尾部，以及评估每个PRS模型的预测性能， 使用拟合优度测量的DS-ALL风险。我们还将检测单核苷酸多态性（SNP） 以前与淋巴细胞性状相关的基因也可能与DS-ALL风险相关。在目标2中，我们将 研究血细胞性状遗传变异与躯体特征和临床结局之间的关系 在DS-ALL患者中。首先，我们将评估MR中是否存在肿瘤亚型特异性相关性。 目标1中确定的分析、PRS和候选SNP，重点关注普遍存在的CRLF 2重排 和IKZF 1缺失。接下来，在仅病例分析中，我们将探讨PRS是否适用于血细胞性状 可能显示与DS-ALL患者临床结局相关，包括治疗相关毒性、复发风险， 和总生存期。这项研究将阐明DS-ALL的病因，并揭示可能导致DS-ALL的新的危险因素。 指导基因检测，并通过识别患有遗传病的儿童，为未来的精确预防方法提供信息 具有最大ALL风险的DS，以及潜在具有高不良结局风险的DS-ALL患者。