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Clinical and biochemical function of polymorphic NR0B1 GGAA-microsatellites in Ewing sarcoma: a report from the Children\u27s Oncology Group.
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
The value of TOP2A as a target for anthracycline-based chemotherapy in advanced endometrial carcinoma (EC): NRG Oncology/Gynecology Oncology Group study.
Tumoral TP53 and/or CDKN2A alterations are not reliable prognostic biomarkers in patients with localized Ewing sarcoma: A report from the Children's Oncology Group
BackgroundA growing collection of retrospective studies have suggested that TP53 mutations and/or CDKN2A deletions have prognostic significance in Ewing sarcoma. We sought to evaluate these variables in patients with localized disease treated prospectively on a single Children's Oncology Group protocol.ProcedureOf the 568 patients enrolled on Children's Oncology Group protocol AEWS0031 (NCT00006734), 112 had tumor specimens of sufficient quality and quantity to allow for analysis of TP53 mutations status by DNA sequencing, and CDKN2A deletion by dual color fluorescent in situ hybridization.ResultsEight of 93 cases (8.6%) were found to have TP53 point mutations and 12 of 107 cases (11.2%) demonstrated homozygous CDKN2A deletion. Two cases were found to have an alteration in both genes. There was no significant difference in event-free survival of patients with TP53 mutations and/or CDKN2A deletions compared to patients with normal TP53/CDKN2A gene status, as demonstrated by log rank test (p = 0.58).ConclusionsAlthough previous retrospective studies suggest their significance, TP53 mutation and/or CDKN2A deletion are not reliable prognostic biomarkers in localized Ewing sarcoma
Clinical and Biochemical Function of Polymorphic <i>NR0B1</i> GGAA-Microsatellites in Ewing Sarcoma: A Report from the Children's Oncology Group
<div><p>Background</p><p>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.</p><p>Objectives</p><p>Here we sought to examine the polymorphic spectrum of a GGAA-microsatellite within the <i>NR0B1</i> promoter (a critical EWS/FLI target) in primary Ewing sarcoma tumors, and characterize how this polymorphism influences gene expression and clinical outcomes.</p><p>Results</p><p>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 <i>NR0B1</i> 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 <i>NR0B1</i> GGAA-microsatellite polymorphisms and survival outcomes.</p><p>Conclusions</p><p>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.</p></div
NR0B1 GGAA-microsatellite sequence characteristics in Ewing sarcoma tumors and healthy controls.
<p>*Mean values ± standard deviation.</p
Patient demographics of included and excluded AEWS0031 patients.
<p>*Fisher's exact test.</p
Model of GGAA-microsatellite polymorphism contributions to Ewing sarcoma susceptibility in African and white European populations.
<p>Model of GGAA-microsatellite polymorphism contributions to Ewing sarcoma susceptibility in African and white European populations.</p
Comparison of germline and tumor <i>NR0B1</i> GGAA-microsatellites.
<p>Comparison of germline and tumor <i>NR0B1</i> GGAA-microsatellites.</p
<i>NR0B1</i> GGAA-microsatellites are polymorphic in Ewing sarcoma tumors with an allelic distribution different than that of white European and African controls.
<p>(<b>A</b>) Principal components analysis comparing unique microsatellite haplotypes in tumor samples and white European controls demonstrate three principal sequence clusters, with a high-degree of overlap between the two populations. (<b>B</b>) Histogram plots comparing the distribution frequency of <i>NR0B1</i> GGAA-microsatellite haplotypes in tumors and white European and African controls. Despite the overlapping PCA analysis, an enrichment of haplotypes containing 21–25 and 56–60 GGAA motifs was observed in tumor samples. Relative to white Europeans, a depletion of haplotypes containing 16–20 GGAA motifs was also noted in tumors. (<b>C</b>) Cumulative density plots for each study population similarly demonstrate the enrichment of haplotypes containing 21–25 and 56–60 GGAA motifs in tumors. The distribution of these haplotypes in tumors is significantly different from both white Caucasian and African populations (KS test, p<0.001). (<b>D</b>) Stratifying haplotypes according to the major sequence types identified in the PCA demonstrates that intermediate (3 segment) GGAA-microsatellites are more enriched in tumors and larger multisegment haplotypes (>3 segments) were also more enriched compared to white Europeans, although markedly less than Africans. Control white European and African population data from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104378#pone.0104378-Beck1" target="_blank">[12]</a>.</p