Research in Pediatric Epidemiology & Clinical Research

PI/Contact: Logan Spector - [email protected] - Project Number: 5R01-CA239701 

The major goal is to conduct admixture mapping of acute lymphoblastic leukemia (ALL) risk and
outcome in African-American patients. We have assembled existing DNA samples and data for 930 B-cell acute lymphoblastic leukemia (B-ALL) patients with African-American (AA) ancestry and will additionally accrue ~590 over the life of the project. We 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, we 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. The proposed 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, we 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 outcome among AA children.

PI: Beau Webber - Funding Source: NIH/NCI - Project Number: 5R37-CA276345

Contact: Logan Spector - [email protected] 

Ancestry is in fact the strongest known risk factor for Ewing sarcoma, but the molecular basis of these differences in risk have been investigated only sparingly. As the mechanisms by which EWS-FLI1 interacts with the genome have become clear, it is feasible with an appropriate model to investigate how genomic ancestry in general and at specific loci modulates EWS-FLI1 activity including its downstream effects on epigenetic and transcriptional programs. To this end we have devised a strategy to introduce EWS-FLI1 in derivatives of induced pluripotent stem cells (iPSC) in order to characterize downstream molecular and functional consequences of EWS-FLI1 expression. Using accessible variant array data from several large stem cell repositories we identified banked iPSC lines derived from individuals with a range of European, African, and Amerind ancestry. We will introduce EWS-FLI1 expression at intermediate stages of development relevant to Ewing sarcomagenesis—namely neural crest cells and mesenchymal stem cells. Globally we will examine whether gene expression and chromatin state exhibits similarity to the Ewing expression signature in proportion to European ancestry percentage. Genome-wide chromatin occupancy of EWS-FLI1 will be profiled and its relationship to local ancestry defined using long-read sequencing. Genes that are differentially influenced by EWS-FLI1 in “permissive” (European ancestry), “moderately permissive” (Amerind ancestry) and “impermissive” (African ancestry) genomes will be considered targets of potential therapeutic value and will undergo validation using CRISPR/Cas9 genome engineering and functional assays. The resulting data will represent the first and only effort, to our knowledge, to take advantage of the known differences in risk for Ewing sarcoma by ancestry to study EWS-FLI1 binding and downstream effects. 

PI/Contact: Jen Poynter - [email protected] - Funding Source: NIH/NCI - Project Number: 5R01-CA267938

This study is currently in analysis. The Germ Cell Tumor Epidemiology Study (GaMETES) was designed to try to find out more about risk factors associated with germ cell tumors in children. The main purpose of this study is to understand how genes might affect young people’s chances of developing a germ cell tumor (GCT). To do this we will compare the genes of young people with a GCT to the genes of their parents or unrelated individuals in the population who don’t have a GCT. We are also trying to understand if differences in the tumor samples help us predict which patients will have poor outcomes following standard therapy. Current work is focused on analyzing large genomic datasets, including array genotyping data, whole genome and whole exome sequencing, and DNA methylation.

PI/Contact: Logan Spector - [email protected] - Funding Source: NIH/NCI - Project Number: 5R01-CA266253

The Childhood Cancer and Leukemia International Consortium (CLIC) is ideally suited to understanding the genomic architecture of acute lymphoblastic leukemia (ALL) risk in children of many ancestries. CLIC’s collective genomic datasets comprise ~12,000 children with ALL from five continents, making them both the largest and most diverse such datasets worldwide. With this resource, which more than doubles the sample size over previous GWAS, we propose to: 1) estimate heritability of ALL using SNP-based methods in diverse populations including Africans/African- Americans (AFR), admixed Americans (i.e. Latinos; AMR), East Asians (EAS), Europeans (EUR), Middle Eastern/North Africans (MENA), South Asians (SAS), and Southeast Asians (SEA); 2) conduct comprehensive genomewide and local discovery for variants associated with ALL; and 3) create population-specific polygenic risk scores and examine their relationship to harmonized epidemiologic data within CLIC. At the conclusion of this study, CLIC will have articulated a far more comprehensive genetic epidemiology of ALL than exists today in populations that represent most of the children on earth; and, for the first time, will simultaneously consider non-genetic risk factors. We further will have prioritized candidate variants for functional validation and built a robust infrastructure for future analyses of CLIC’s genomic datasets.

PI/Contact: Jen Poynter - [email protected] - Funding Source: NIH/NCI - Project Number: 5R01-CA142714

This study is currently in analysis. Myelodysplastic syndromes (MDS) are a group of clonal hematologic disorders that result in dysplastic and ineffective hematopoiesis. We have completed the first population-based case control study of adult MDS since it was reclassified as a malignancy. The Adults in Minnesota with Myelodysplastic Syndrome (AIMMS) study includes data on lifestyle factors, occupational exposures, array genotyping and detailed survival data. We also have data available for a large case series of pediatric MDS patients including demographic, outcomes and genetic data. Current study activities include analysis of array genotyping and targeted sequencing data to evaluate germline and somatic alterations in pediatric and adult MDS patients.

PI/Contact: Erin Marcotte - [email protected] - Funding Source: NIH/NCI - Project Number: R01-CA269393

This project aims to explore the link between the ETV6/RUNX1 translocation at birth and the risk of childhood leukemia. Leukemia is the most common cancer in children, making up about one-third of cancer cases in kids aged 0-14. Research shows that acute lymphoblastic leukemia (ALL), the most prevalent type, often initiates before birth in some children. These children have a pre-leukemic condition, and we need to understand its causes and how it progresses to ALL. We have developed a new method to detect ETV6/RUNX1 pre-leukemia using newborn blood spots. Our goals are to: 1) analyze blood spots from 500 children who later developed leukemia and 3,000 healthy children to identify factors related to pre-leukemia at birth; 2) assess the risk of ALL associated with pre-leukemia; and 3) track how long pre-leukemia lasts in early childhood using blood samples collected over time. This study will help us understand how many children with ALL were born with the gene fusion, what factors predict pre-leukemia, and how long it persists. It will be the first to monitor pre-leukemia in early childhood, providing valuable insights into pediatric cancer. Successful completion could lead to better clinical monitoring for high-risk infants and advance our understanding of childhood leukemia.

PI/Contact: Erin Marcotte - [email protected] - Funding Source: NIH/NCI - Project Number: R01-CA266105

This project aims to understand the factors behind disparities in childhood cancer relapse, survival, and toxicities. While childhood cancer survival rates have improved, significant racial, ethnic, and socioeconomic gaps remain. Non-Hispanic black and Hispanic children often have lower survival rates, especially for leukemia, compared to non-Hispanic white children. The reasons for these differences are not well understood and may involve both biological and socioeconomic factors. We will collaborate with the Minnesota Population Center to geocode patients from the Childhood Cancer Registration Network (CCRN) and analyze socioeconomic status (SES) data. Our study will focus on over 12,000 acute lymphoblastic leukemia (ALL) patients to explore how SES affects treatment outcomes, including the risk of relapse and survival. This research will be the first large-scale analysis of SES as a predictor of childhood cancer outcomes within the Children's Oncology Group. It will also look at short-term treatment side effects related to SES. Our findings could lead to targeted interventions for low-resource populations and will include follow-up data linked to the National Death Index to track long-term survival. Ultimately, this project aims to better understand the factors contributing to disparities in childhood cancer and improve follow-up care and interventions for survivors.