Molecular epidemiology of acute lymphoblastic leukemia in children with Down syndrome

唐氏综合症儿童急性淋巴细胞白血病的分子流行病学

• 批准号: 10885331
• 负责人: Philip Lupo
• 金额: $ 84.4万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-03 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10885331
• 关键词: Acute Lymphocytic Leukemia; Alleles; Automobile Driving; Binding; Biology; CDKN2A gene; Cell Cycle; Cellular Assay; Cessation of life; Child; Childhood Leukemia; Chromosome 21; Chronic; Clinical; Clinical Trials Cooperative Group; Congenital Abnormality; Cytogenetics; Data; Development; Down Syndrome; Enrollment; Epigenetic Process; Exhibits; Family; Gene Dosage; Gene Expression; Genes; Genetic; Genetic Counseling; Genetic Variation; Genome; Genomics; Germ-Line Mutation; Health; Heritability; Immunophenotyping; Inherited; Letters; Medical Records; Molecular; Molecular Epidemiology; Outcome; Patients; Pattern; Pediatric Oncology Group; Phenotype; Predisposition; Proliferating; Protocols documentation; Questionnaires; Registries; Relapse; Resources; Risk; Risk Factors; Role; Sampling; Specimen; Structural Congenital Anomalies; Susceptibility Gene; Testing; Toxic effect; Treatment outcome; United States National Institutes of Health; Variant; cohort; dosage; genetic testing; genetic variant; genome sequencing; genome wide association study; genome-wide analysis; high risk; improved; improved outcome; indexing; insight; leukemia; lifetime risk; lymphoblastoid cell line; mortality; patient population; targeted treatment; transcription factor; transcriptome sequencing; transcriptomics; variant of interest; whole genome

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.

修改项目摘要/摘要部分 唐氏综合征（DS）是急性淋巴细胞白血病（ALL）最强的危险因素之一， 20-与没有DS的儿童相比，风险增加了一倍。DS-ALL儿童的生存率仍为10-20% 低于非DS-ALL患者，由于复发和毒性。患有DS的儿童也有一个 几种出生缺陷和慢性健康状况的风险增加。尽管这些风险增加， 几十年来，白血病风险增加的基础仍然不清楚， 缺乏探索其他DS表型特征与ALL易感性之间相互作用的研究。而 增加21号染色体基因的剂量可能有助于ALL风险，单独的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 和其他DS相关表型与21三体综合征的组合影响ALL的易感性。我们 到目前为止已经提出了几个重要的意见。1)在第一个DS-ALL的全基因组关联研究中， 我们观察到ALL易感基因中的基因座（例如，CDKN 2A，IKZF 1）对ALL风险的影响更强， 与没有DS的儿童相比。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，这可能表明ALL- 易感表型与其他综合征特征。这些观察结果表明， 21三体背景下的ALL易感性。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）遗传性遗传变异和 体细胞基因组异常，或3）其他DS相关表型对白血病易感性的作用， 结果。通过NIH INCLUDE和Kids First机制，我们和合作者发起了大型的 2,500名DS儿童（约400名ALL儿童）的大规模基因组测序。利用这一前所未有的 基因组分析和独特的DS队列，本研究的目的是确定分子水平， DS儿童ALL的基础;并确定DS相关表型是否与 ALL风险和/或结局（毒性、复发和生存）。为了实现这些目标， 本研究的目的是：1）对与ALL风险相关的遗传变异进行全面分析， 患有DS的儿童，重点是结构，罕见和21号染色体变异; 2）进行深入研究 对DS-ALL儿童进行表型分型，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DS儿童的风险增加的基本问题 他们的白血病与没有DS的儿童的白血病有何不同，以及其他DS相关表型如何可能 影响ALL易感性、生存率和毒性。这项研究的结果可能会改善遗传 测试和咨询策略与DS儿童。对驱动DS-ALL的基因的深入了解可以指导 靶向疗法的开发。

项目成果

Co-occurrence of congenital anomalies by maternal race/ethnicity among infants and fetuses with Down syndrome, 2013-2017: A U.S. population-based analysis.

• DOI: 10.1002/bdr2.1975
• 发表时间: 2022-01-15
• 期刊: Birth defects research
• 影响因子: 2.1
• 作者: Stallings EB;Isenburg JL;Heinke D;Sherman SL;Kirby RS;Lupo PJ;National Birth Defects Prevention Network
• 通讯作者: National Birth Defects Prevention Network

The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis.

• DOI: 10.1038/s41467-021-21064-z
• 发表时间: 2021-02-05
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Muskens IS;Li S;Jackson T;Elliot N;Hansen HM;Myint SS;Pandey P;Schraw JM;Roy R;Anguiano J;Goudevenou K;Siegmund KD;Lupo PJ;de Bruijn MFTR;Walsh KM;Vyas P;Ma X;Roy A;Roberts I;Wiemels JL;de Smith AJ
• 通讯作者: de Smith AJ