Effects of germline GATA3 variants on ALL somatic genomics and prognosis in multi-ethnic populations

种系 GATA3 变异对多种族人群中 ALL 体细胞基因组学和预后的影响

• 批准号: 10390748
• 负责人: Philip Lupo
• 金额: $ 30万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 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/10390748
• 关键词: Acute Lymphocytic Leukemia; Acute leukemia; Budgets; Cessation of life; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Classification; Clinical; Clinical Data; Clinical Trials; Cohort Studies; Diagnosis; Disease; Disease-Free Survival; Early treatment; Epidemiology; Ethnic group; European; Face; GATA3 gene; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genetic study; Genets; Genomics; Genotype; Goals; Hispanic; Hispanic Populations; Incidence; Inferior; Inherited; Investments; Knowledge; Lead; Lymphoblastic Leukemia; Malignant Childhood Neoplasm; Medical Genetics; Modeling; Not Hispanic or Latino; Odds Ratio; Outcome; Pathogenesis; Patients; Pediatric Oncology Group; Pediatric cohort; Population; Positioning Attribute; Predisposition; Prognosis; Prognostic Factor; Relapse; Reporting; Research; Research Personnel; Residual Neoplasm; Resources; Risk; Risk Factors; Sampling; Socioeconomic Factors; Specimen; Survival Rate; Susceptibility Gene; Testing; Therapeutic Trials; Time; Treatment Protocols; Treatment outcome; United States National Institutes of Health; Variant; Work; cancer health disparity; cohort; cost; cost effective; data repository; disorder risk; ethnic disparity; experience; genetic analysis; genetic epidemiology; genetic variant; genome wide association study; genomic data; genomic locus; high risk; improved; improved outcome; indexing; insight; leukemia; leukemia relapse; multi-ethnic; multidisciplinary; novel; prognostic; prognostic value; racial disparity; response; risk stratification; risk variant; skills; socioeconomic disparity; socioeconomics; treatment response

Abstract Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and the leading cause of disease-related death among children in the US. Taking a genome-wide association study (GWAS) approach, we and others have identified 17 genomic loci associated with susceptibility to ALL in children. In particular, our group reported germline genetic variants in the GATA3 gene that strongly influence the risk of developing Ph-like ALL, a novel and high-risk subtype of this pediatric cancer (Nat Genet 45:1494). Additionally, and importantly, GATA3 variants are also related to poor response to ALL therapy, high relapse rate, and are over-represented in Hispanic children, who face inferior survival relative to non-Hispanic whites. The potential prognostic value of GATA3 distinguishes this gene from the majority of ALL susceptibility genes identified thus far and points to the possibility of incorporating germline genetic factors into ALL risk stratification to further individualize leukemia therapy. However, a number of knowledge gaps exist: 1) we have yet to comprehensively examine ALL risk variants in GATA3 beyond the index SNP in the original GWAS; 2) the association of GATA3 variants with different subtypes within Ph-like ALL is incompletely understood, and 3) there is no study to compare germline GATA3 variants, somatic genomic features, and clinical variables for their relative and independent prognostic impacts in the context of contemporary ALL treatment regimens. Therefore, we hypothesize that germline GATA3 variants are independent prognostic factors in pediatric ALL and can be used to further improve risk classification, particularly among Hispanics. Collaborating with the Children's Oncology Group (COG), we will first comprehensively examine GATA3 germline polymorphisms and test their association with ALL genomic abnormalities in two national ALL frontline trials (AALL0331 and AALL1131 trials, N=4,062). Focusing on these two large clinical trials, we will evaluate effects of GATA3 variants on early treatment response, ALL relapse, and event-free survival, in conjunction with somatic genomic factors and clinical presenting features. Lastly, we will explore the contribution of GATA3 variants to inferior ALL outcome in Hispanics, utilizing the national epidemiologic cohort for pediatric leukemia disparities research, namely the REDIAL consortium (N=1,000) by integrating clinical, genetic, and socioeconomic variables. Our long-term goal is to integrate germline genetic factors such as GATA3 variants into ALL risk stratification to improve outcome, which represents a significant shift from the current paradigm that relies entirely on somatic genomics and clinical features. Here, we comprehensively leverage the NIH's investment in national pediatric ALL trials and also state-of-the-art genomic datasets related to ALL, thus making this project feasible within this time frame and also cost-effective.

摘要 急性淋巴细胞白血病（ALL）是最常见的儿科癌症，也是疾病相关性白血病的主要原因。 美国儿童死亡率。采用全基因组关联研究（GWAS）方法，我们和其他人已经 确定了17个与儿童ALL易感性相关的基因组位点。特别是，我们的小组报告说， GATA 3基因中的遗传变异强烈影响发生Ph样ALL的风险，这是一种新的高风险 这种儿科癌症的亚型（Nat Genet 45：1494）。此外，重要的是，GATA 3变体也与 对ALL治疗反应差，复发率高，并且在西班牙裔儿童中占主导地位，他们面临着劣势 相对于非西班牙裔白人的生存率。GATA 3的潜在预后价值将该基因与其他基因区分开来。 迄今为止，大多数ALL易感基因已被鉴定，并指出了将生殖系基因整合到 将遗传因素纳入ALL风险分层，以进一步个性化白血病治疗。但若干 存在知识差距：1）我们尚未全面检查GATA 3中的所有风险变体， 原始GWAS中的SNP; 2）GATA 3变体与Ph样ALL中不同亚型的相关性， 不完全理解，和3）没有研究比较生殖系GATA 3变体，体细胞基因组 特征和临床变量，以确定其在以下背景下的相对和独立预后影响： 当代ALL治疗方案。因此，我们假设生殖系GATA 3变异体是 儿童ALL的独立预后因素，可用于进一步改善风险分类， 在西班牙裔中。与儿童肿瘤学小组（COG）合作，我们将首先全面检查 两个国家ALL患者GATA 3种系多态性及其与ALL基因组异常的关系 一线试验（AALL 0331和AALL 1131试验，N= 4，062）。围绕这两项大型临床试验，我们将评估 GATA 3变异体对早期治疗应答、ALL复发和无事件生存期的影响， 体细胞基因组因素和临床表现特征。最后，我们将探讨GATA 3变体的贡献。 在西班牙裔人群中，使用国家流行病学队列研究儿童白血病差异， 研究，即REDIAL联盟（N= 1，000），通过整合临床，遗传和社会经济变量。 我们的长期目标是将生殖系遗传因素如GATA 3变异整合到ALL风险分层中， 改善结果，这代表了从目前完全依赖于体细胞的范式的重大转变 基因组学和临床特征。在这里，我们全面利用国家卫生研究院在国家儿科的投资， ALL试验以及与ALL相关的最先进的基因组数据集，从而使该项目在此范围内可行。 时间框架和成本效益。