Dataset Information

Clinical and biochemical function of polymorphic NR0B1 GGAA-microsatellites in Ewing sarcoma: a report from the Children's Oncology Group.

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.

SUBMITTER: Monument MJ

PROVIDER: S-EPMC4122435 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Clinical and biochemical function of polymorphic NR0B1 GGAA-microsatellites in Ewing sarcoma: a report from the Children's Oncology Group.

Monument Michael J MJ Johnson Kirsten M KM McIlvaine Elizabeth E Abegglen Lisa L Watkins W Scott WS Jorde Lynn B LB Womer Richard B RB Beeler Natalie N Monovich Laura L Lawlor Elizabeth R ER Bridge Julia A JA Schiffman Joshua D JD Krailo Mark D MD Randall R Lor RL Lessnick Stephen L SL

PloS one 20140805 8

<h4>Background</h4>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.<h4>Objectives</h4>Here we sought to examine the polymorphic spe ...[more]

PMID: 25093581

Similar Datasets

Project description:Advances in molecular diagnostics have identified subsets of Ewing and Ewing-like sarcomas driven by variant translocations with unique biology. It is likely that patients with these tumours will have different clinical features and therapeutic outcomes. Nevertheless, the management of these patients both locally and within cooperative group trials depends on the local pathological diagnosis. It is not known what molecular diagnostic approaches are employed by local pathologists or if the exact translocation is commonly determined. In addition, it is not known what therapeutic approaches are employed for these patients or what cooperative trials are deemed appropriate for these patients by expert consensus. To answer these questions, we performed an international survey of oncologists and pathologists to better understand the diagnostic approaches used to identify variant translocations and the influence the findings have on therapy and clinical trial eligibility. An online survey was distributed to oncologists and pathologists primarily in North America. A total of 141 surveys were completed, representing a 28% response rate. The majority of respondents considered EWSR1-ETS gene family translocations (range 61-96%) to be Ewing sarcoma and would include them on the primary arm of a Ewing sarcoma clinical trial. There was a lack of consensus on how to classify and stratify BCOR-CCNB3, CIC-DUX4, and EWSR1+ with non-ETS partner fusions. Most respondents were either unsure how their institution tested, or their institution did not perform the test. In cases with atypical Ewing morphology, most respondents favoured additional fusion transcript testing. There is a lack of consensus regarding the classification and stratification of rare molecular subtypes in Ewing sarcoma. It is not clear how these alternative translocations have impacted outcomes for past clinical studies. This suggests a need for molecular confirmation of diagnoses and centralized or minimum standardization of testing for future trial enrolment.

Dataset Information

Clinical and biochemical function of polymorphic NR0B1 GGAA-microsatellites in Ewing sarcoma: a report from the Children's Oncology Group.

Background

Objectives

Results

Conclusions

Publications

Clinical and biochemical function of polymorphic NR0B1 GGAA-microsatellites in Ewing sarcoma: a report from the Children's Oncology Group.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets