Understanding the Increased Risk of Childhood Acute Lymphoblastic Leukemia in Latinos

了解拉丁裔儿童儿童急性淋巴细胞白血病风险增加

• 批准号: 10440966
• 负责人: Adam De Smith
• 金额: $ 74.6万
• 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: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440966
• 关键词: Accounting; Acute Lymphocytic Leukemia; Admixture; Americas; Awareness; California; Cesarean section; Cessation of life; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Cytomegalovirus Infections; Data; Environmental Exposure; Environmental Risk Factor; Epidemiology; Ethnic Origin; Etiology; European; Exhibits; Face; Future; GATA3 gene; Gene Expression; Gene Frequency; General Population; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genome; Genomic Segment; Goals; Guatemala; Heritability; Human; Immune; Immune response; Immunological Models; Incidence; Infection; Inferior; Knowledge; Latino; Latino Population; Lead; Light; Linkage Disequilibrium; Malignant Childhood Neoplasm; Malignant Neoplasms; Meta-Analysis; Modeling; Morbidity - disease rate; Native American Ancestry; Native Americans; Natural Selections; Nature; Outcome; Pediatric Oncology Group; Play; Population; Prevention; Quantitative Trait Loci; Recording of previous events; Reporting; Risk; Risk Factors; Role; Saint Jude Children' s Research Hospital; Sample Size; Survivors; Susceptibility Gene; Testing; Texas; Trees; United States; Variant; Vulnerable Populations; Weight; admixture mapping; case control; causal variant; disorder prevention; epidemiology study; ethnic disparity; genetic risk assessment; genetic variant; genome wide association study; genome-wide; high risk; improved; in utero; insight; modifiable risk; novel; polygenic risk score; risk mitigation; risk prediction; risk stratification; risk variant; transcriptome; transcriptomics

ABSTRACT Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and, despite advances in treatment, it is still one of the leading causes of childhood death in the United States (US), and survivors face significant lifelong treatment-related morbidities. Children of Latino ethnicity have the highest and fastest-increasing risk of ALL in the US, and have lower survival than non-Latino whites; however, this ethnic disparity in incidence and outcome is not fully understood. Elucidating the increased risk of ALL in Latino children may reveal novel insights in the etiology of ALL in both Latino and non-Latino populations, and may highlight potential avenues for disease prevention. We hypothesize that germline genetic variation plays an essential role in the increased ALL risk in Latinos, that this risk is imparted via Native American ancestry, and that ALL risk alleles were selected in Native Americans during European colonization of the Americas due to their beneficial effects on immune response to new infections. We have assembled the largest ever case-control set of childhood ALL in Latinos, including over 5,400 cases and 27,000 controls from three independent studies in California, plus studies in Texas, Children’s Oncology Group/St. Jude Children’s Research Hospital, and Guatemala. In our first aim, we will perform three complementary approaches to discover novel common risk loci associated with childhood ALL: i) a genome- wide association study (GWAS) meta-analysis, ii) admixture mapping to capitalize on the recently admixed nature of Latino genomes, and iii) a transcriptome-wide association study to identify novel loci and to pinpoint causal genes at known and novel risk regions. In our second aim, we will characterize the genetic variants in terms of their association with local Native American ancestry and whether they exhibit evidence of directional natural selection on the Native American branch of the human population tree. We will also characterize the aggregate effects of common variants on childhood ALL risk and how this varies by ethnicity, via comprehensive modeling of polygenic risk scores (PRS) for ALL in Latinos and in non-Latino whites. Finally, we will incorporate our genetic findings into epidemiologic analyses, by accounting for common (PRS) genetic variants in ALL risk models for immune-related risk factors in Latinos and non-Latino whites, including cesarean delivery and in utero cytomegalovirus infection, both of which have shown stronger effects on ALL risk in Latinos and are potentially modifiable risk factors. The results of this study will shed light on the etiology of childhood ALL in general and of the increased risk of ALL in Latino children, which will help to alleviate this ethnic disparity and may inform future approaches for childhood leukemia prevention.

摘要