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 急性淋巴细胞性白血病(ALL)是儿科最常见的癌症，也是与疾病相关的主要原因 美国儿童死亡事件。采取全基因组关联研究(GWAS)的方法，我们和其他人 确定了17个与儿童急性淋巴细胞白血病易感性相关的基因组基因座。特别是，我们小组报告了生殖系 GATA3基因的遗传变异强烈影响发生Ph样ALL的风险，Ph样ALL是一种新的高危疾病 这种儿童癌症的亚型(NAT Genet 45：1494)。此外，重要的是，GATA3变体也与 对所有治疗反应差，复发率高，在西班牙裔儿童中表现过度，他们面临劣势 相对于非西班牙裔白人的生存。GATA3的潜在预后价值使该基因有别于 到目前为止发现的所有易感基因中的大多数，并表明有可能整合生殖系 将遗传因素纳入所有危险分层，进一步实现白血病个体化治疗。然而，一些人 知识差距存在：1)我们尚未全面检查GATA3中除指数之外的所有风险变量 2)Ph-like ALL中具有不同亚型的GATA3变异体的关联 不完全了解，以及3)没有研究比较生殖系GATA3变体、体细胞基因组 的特征和临床变量的相对和独立的预后影响的背景下 当代所有治疗方案。因此，我们假设生殖系GATA3变种是 儿童急性淋巴细胞白血病的独立预后因素，可用于进一步改进风险分类，特别是 在西班牙裔美国人中。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GATA3胚系基因多态性及其与所有基因组异常的相关性 一线试验(AALL0331和AALL1131试验，N=4,062)。围绕这两个大型临床试验，我们将评估 GATA3变异对早期治疗反应、ALL复发和无事件生存率的影响 体细胞基因组因子与临床表现特征。最后，我们将探讨GATA3变体的贡献 在拉美裔美国人中，利用国家流行病学队列研究儿童白血病的差异 研究，即通过整合临床、遗传和社会经济变量的Rial联合体(N=1,000)。 我们的长期目标是将生殖系遗传因素(如GATA3变体)整合到所有风险分层中，以 改善结果，这代表着与目前完全依赖躯体的范式的重大转变 基因组学和临床特征。在这里，我们全面利用NIH在国家儿科领域的投资 所有试验以及与ALL相关的最先进的基因组数据集，从而使该项目在 时间框架和成本效益也很高。