These researcher are using MSI resources for three projects concerning childhood cancers:
- Acute lymphoblastic leukemia (ALL):
ALL is the most common form of pediatric cancer, and a leading cause of death in children. There are conflicting reports on the role of KIR-HLA in pediatric ALL and to date there have been no studies that have simultaneously considered CMV and these functional genetic variants in innate immunity. To confirm an association of congenital CMV infection and ALL and to clarify the role of KIR-HLA in pediatric ALL, these researchers are conducting a population-based study of 1,158 cases and controls matched 4:1 on sex, race/ethnicity, and year of birth obtained from the Michigan BioTrust for Health. The group's specific aims are to:
- Compare CMV prevalence at birth in newborn DBS of ALL cases to that in controls
- Compare KIR-HLA genotypes among cases and controls.
In addition there are two exploratory aims:
- Examine whether KIR-HLA genetics modify the association between congenital CMV infection and ALL
- Describe the association of KIR-HLA variants with CMV prevalence at birth
Confirmation of an association between congenital CMV infection and development of ALL will for the first time establish a potentially modifiable risk factor for the most common childhood cancer, as well as adding urgency to ongoing efforts to detect and mitigate the effects of congenital CMV infection.
- Ewing sarcoma (ES):
ES is a rare but deadly bone tumor which occurs mainly in adolescents and young adults. As survival for ES has not improved beyond ~60% in the last few decades, it is critical to understand its origins in order to improve therapy. Most attempts to determine the cell of origin of ES have relied on cells transformed by the EWS-FLI1 fusion protein, which exerts a strong transcriptional program, whereas these researchers propose a method that uses untransformed candidate cell types. They will derive induced pluripotent stem cells (iPSC) or obtain primary cells for the following cell types: undifferentiated iPSC, iPS-mesenchymal stem cells, bone marrow- derived mesenchymal stem cells, neural crest progenitors, and neural-crest/mesenchymal stem cells. An open chromatin profile of each cell type will be obtained via the ATAC-seq assay and cross referenced with a genomewide case-control dataset on ES to nominate a cell of origin. Lastly, variants in open chromatin in the nominated cell of origin will be comprehensively characterized. This research represents a novel method for determining the cell of origin for ES, which if successful would point the way to more precise animal models of the disease and potentially inform the development of therapy.
- B-cell lymphoblastic leukemia (B-ALL):
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. This is true both in international comparisons of rates of ALL in African nations to those elsewhere, and in comparing rate of B-ALL in African-American (AA) children to that in European-American (EA) children in the United States. The inverse association of African ancestry with incidence of B-ALL is independent of established perinatal risk factors for the disease. Moreover, AA children have lower incidence despite having greater exposure to many putatively causal environmental risk factors for B-ALL than do EA children. Common genetic variants established by genomewide association studies incompletely explain the deficit of B-ALL in AA children, suggesting undiscovered contributing genetic factors may be detected by admixture mapping. These researchers have assembled existing DNA samples and data for 930 B-ALL patients with AA ancestry and will additionally accrue ~590 over the life of the project. They will conduct 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, they will examine 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. This research will potentially answer a long- standing mystery by revealing critical genes or loci that explain the comparative deficit of B-ALL in AA compared to EA children. In addition, the researchers may uncover genes or variants associated with the worse characteristics at presentation in AA patients as well as with worse survival, which will indicate avenues for improving outcomes among AA children.