Clinical and Biochemical Function of Polymorphic NR0B1 GGAA-microsatellites in Ewing Sarcoma: a Report from the Children's Oncology Group

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2014 Aug 6

PMID 25093581

Citations 26

Authors

Michael J Monument

Kirsten M Johnson

Elizabeth McIlvaine

Lisa Abegglen

W Scott Watkins

Lynn B Jorde

Richard B Womer

Natalie Beeler

Laura Monovich

Elizabeth R Lawlor

Julia A Bridge

Joshua D Schiffman

Mark D Krailo

R Lor Randall

Stephen L Lessnick

Affiliations

Soon will be listed here.

Abstract

Background: The genetics involved in Ewing sarcoma susceptibility and prognosis are poorly understood. EWS/FLI and related EWS/ETS chimeras upregulate numerous gene targets via promoter-based GGAA-microsatellite response elements. These microsatellites are highly polymorphic in humans, and preliminary evidence suggests EWS/FLI-mediated gene expression is highly dependent on the number of GGAA motifs within the microsatellite.

Objectives: Here we sought to examine the polymorphic spectrum of a GGAA-microsatellite within the NR0B1 promoter (a critical EWS/FLI target) in primary Ewing sarcoma tumors, and characterize how this polymorphism influences gene expression and clinical outcomes.

Results: A complex, bimodal pattern of EWS/FLI-mediated gene expression was observed across a wide range of GGAA motifs, with maximal expression observed in constructs containing 20-26 GGAA motifs. Relative to white European and African controls, the NR0B1 GGAA-microsatellite in tumor cells demonstrated a strong bias for haplotypes containing 21-25 GGAA motifs suggesting a relationship between microsatellite function and disease susceptibility. This selection bias was not a product of microsatellite instability in tumor samples, nor was there a correlation between NR0B1 GGAA-microsatellite polymorphisms and survival outcomes.

Conclusions: These data suggest that GGAA-microsatellite polymorphisms observed in human populations modulate EWS/FLI-mediated gene expression and may influence disease susceptibility in Ewing sarcoma.

Citing Articles

EWS/FLI1 Characterization, Activation, Repression, Target Genes and Therapeutic Opportunities in Ewing Sarcoma.

Yasir M, Park J, Chun W Int J Mol Sci. 2023; 24(20).

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Targeted Therapy for EWS-FLI1 in Ewing Sarcoma.

Gong H, Xue B, Ru J, Pei G, Li Y Cancers (Basel). 2023; 15(16).

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Human EWS-FLI protein recapitulates in Drosophila the neomorphic functions that induce Ewing sarcoma tumorigenesis.

Molnar C, Reina J, Herrero A, Heinen J, Mendiz V, Bonnal S PNAS Nexus. 2023; 1(4):pgac222.

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ETV6 dependency in Ewing sarcoma by antagonism of EWS-FLI1-mediated enhancer activation.

Gao Y, He X, Wu X, Huang Y, Toneyan S, Ha T Nat Cell Biol. 2023; 25(2):298-308.

PMID: 36658219 PMC: 10101761. DOI: 10.1038/s41556-022-01060-1.

Systematic multi-omics cell line profiling uncovers principles of Ewing sarcoma fusion oncogene-mediated gene regulation.

Orth M, Surdez D, Faehling T, Ehlers A, Marchetto A, Grossetete S Cell Rep. 2022; 41(10):111761.

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