Ewing Sarcoma Genome-wide Association Study
Manhattan plot of meta-analysis –log10 P-values for the association of each SNP with EWS risk (Machiela et al, Nat Comms 2018)
Overview
Ewing sarcoma (EwS) is a pediatric bone and soft tissue tumor for which genetic risk factors remain poorly understood. DCEG investigators are studying inherited genetic variation to identify regions in the genome associated with increased risk of EwS. They accomplish this by comparing the frequency of genotyped genetic variants between EwS cases and ancestry-matched, cancer-free controls to identify genomic regions that are important for EwS susceptibility.
This large (2,000+ cases), international consortium combines previously published data with new EwS cases to perform integrative analyses of newly discovered genetic susceptibility regions to identify local genomic structures and nearby target genes that may be important for EWS risk. The overall goal of the study is to expand understanding of EwS etiology and provide insight into improved treatment and potentially preventative measures to reduce the overall burden of EwS.
Study Team
Principal Investigator: Mitchell Machiela
Branch: Integrative Tumor Epidemiology
Study Results & Select Publications
In a pooled analysis of cases, investigators identified three new common, inherited loci, and validated three previously reported susceptibility regions that confer risk for EwS for which genetic risk factors were poorly understood. They found surprising risk effects from the six susceptibility loci, given the relatively small number of cases—odds ratios of 1.7, unusually high for results from a GWAS, and interactions between inherited variation and the acquired EWSR1-FLI1 translocation carried by the majority of EwS cases. Because the absolute risk for EwS is low, population-based screening with these six variants is unlikely to be effective.
Select Publications
- Spector LG, et al. Comparative international incidence of Ewing sarcoma 1988 to 2012. Int J Cancer. 2021.
- Machiela MJet al. Germline variation and somatic alterations in Ewing sarcoma. Methods Mol Biol. 2021.
- Lin S, et al. Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma. PLoS One. 2020.
- Machiela MJ, et al. Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility. Nat Commun. 2018.
- Grünewald TGP, et al. Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite. Nat Genet. 2015.