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.

修改的项目摘要/摘要部分

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