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.

抽象的 急性淋巴细胞白血病 (ALL) 是最常见的儿童恶性肿瘤，患有唐氏综合症的儿童 综合征 (DS) 使罹患 ALL (DS-ALL) 的风险增加高达 30 倍。 DS-ALL 患者还患有 与 ALL 患者相比，治疗相关毒性增加、复发风险增加、总体生存率更差 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 号染色体组成型三体性之外，对于 DS-ALL 的遗传风险知之甚少。 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 对没有 DS 的儿童的血细胞特征和 ALL 进行孟德尔随机化 (MR) 分析，我们发现 总体上以及与其他血细胞类型相关的淋巴细胞过度产生的遗传倾向是 与 ALL 风险增加有因果关系。基于这一发现，并考虑到我们最近的演示 与 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 个 DS-ALL 病例和超过 1500 个 DS 的全基因组测序 (WGS) 数据进行 通过 Gabriella Miller Kids First 和 NIH INCLUDE 计划生成的控制措施，并将公开 可通过 dbGaP 和 Kids First 数据门户获取。在目标 1 中，我们将使用种系 WGS 数据来执行 DS-ALL 的 GWAS，然后使用该 GWAS 的汇总统计数据执行两个样本 MR 分析 血细胞特征和 DS-ALL 风险，使用我们最近在非- MR 研究中开发的遗传仪器 DS 全部。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 全部位于 PRS 分布的尾部，并评估每个 PRS 模型的预测性能 使用拟合优度测量的 DS-ALL 风险。我们还将测试单核苷酸多态性（SNP）是否 先前与淋巴细胞特征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果之间的关联 DS-ALL 患者。首先，我们将评估 MR 中是否可能存在肿瘤亚型特异性关联 分析、PRS 和目标 1 中确定的候选 SNP，重点关注普遍的 CRLF2 重排 DS-ALL 中 IKZF1 缺失。接下来，在仅案例分析中，我们将探讨 PRS 是否适用于血细胞特征 可能与 DS-ALL 患者的临床结果相关，包括治疗相关的毒性、复发风险、 和总体生存率。这项研究将揭示 DS-ALL 的病因，并揭示可能的新危险因素 通过识别患有此类疾病的儿童来指导基因检测并为未来的精准预防方法提供信息 患有 ALL 风险最高的 DS 以及潜在的不良后果高风险的 DS-ALL 患者。