Sex and racial/ethnic differences in B-ALL genomics

点击翻译按钮获取中文摘要

Project Summary Children with substantial African ancestry have long been known to have half or less the rate of B- cell acute lymphoblastic leukemia (B-ALL) than do children with other continental ancestries. Moreover, AA children have lower incidence despite having greater exposure to many putatively causal environmental risk factors for B-ALL than do white children. However, even within AA children, we still observe a 30% excess incidence of ALL among males compared to females at all ages and a remarkable 300% increased incidence at 12 years of age. The male excess may depend on sex-varying associations with the disease for germline genetics on the autosomes and the X chromosome, sex differences in immune function, and/or hormonal differences. Common genetic variants established by genomewide association studies (GWAS) incompletely explain the deficit of B-ALL in AA children, suggesting undiscovered contributing genetic factors may be detected by admixture mapping. Few studies examine GWAS by sex. The parent R01 of this Administrative Supplement, titled “Admixture analysis of acute lymphoblastic leukemia in African American children: the ADMIRAL Study” (R01 CA239701), includes existing DNA samples and data for 930 B-ALL patients with AA ancestry and will accrue ~600 samples over the remaining project years. We are conducting admixture mapping in the assembled group of patients to detect new genetic loci and new variants at established loci associated with occurrence of B-ALL. In addition, we are examining admixture in association with clinical characteristics at diagnosis and survival. Candidate genes/variants will be functionally evaluated through both in silico and in vitro techniques. For the Administrative Supplement, we will conduct sex-stratified GWAS in AA children with B-ALL from the parent R01 and we will expand our analyses to include the X chromosome, which is generally excluded from GWAS. As part of this Award, we will generate a new source of genomic data from healthy AA children using umbilical cord hematopoietic stem cells, which we will use to map sex-differential expression quantitative trait loci for each sex thereby decreasing our search space for disease- relevant loci and increase our power to identify biologically relevant loci in AA males and females with B-ALL. Findings will be placed in context to those observed in AA children that we are currently generating as part of our other funded research. The proposed research will potentially answer a long-standing mystery by revealing critical genes or loci that may explain increased incidence of B-ALL in AA males. Identifying sex-varying associations between germline SNVs and childhood ALL will allow us to identify biologic mechanisms contributing to the observed sex differences in AA B-ALL incidence.