title: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Sarcoma Services, Department of Orthopedic Surgery, University of Utah, Salt Lake City, Utah, United States of America; Center for Children's Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Monument
authors.affiliation: Center for Children's Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Johnson
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McIlvaine
authors.affiliation: Center for Children's Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Abegglen
authors.affiliation: Department of Human Genetics and Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: W Scott
authors.initials: WS
authors.lastname: Watkins
authors.affiliation: Department of Human Genetics and Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Jorde
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Womer
authors.affiliation: Children's Oncology Group Biopathology Center, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.
authors.forename: Natalie
authors.initials: N
authors.lastname: Beeler
authors.affiliation: Children's Oncology Group Biopathology Center, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.
authors.forename: Laura
authors.initials: L
authors.lastname: Monovich
authors.affiliation: Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Lawlor
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Bridge
authors.affiliation: Center for Children's Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States of America; Division of Pediatric Hematology/Oncology, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Schiffman
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Krailo
authors.affiliation: Sarcoma Services, Department of Orthopedic Surgery, University of Utah, Salt Lake City, Utah, United States of America; Center for Children's Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: R Lor
authors.initials: RL
authors.lastname: Randall
authors.affiliation: Sarcoma Services, Department of Orthopedic Surgery, University of Utah, Salt Lake City, Utah, United States of America; Center for Children's Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States of America; Division of Pediatric Hematology/Oncology, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Lessnick
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000483:Alleles; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D057137:DAX-1 Orphan Nuclear Receptor / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D056426:Genetic Loci; D023281:Genomics; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008954:Models, Biological; D059372:Nucleotide Motifs; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D011379:Prognosis; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000378:metabolism; D034802:RNA-Binding Protein EWS / Q000235:genetics / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D055815:Young Adult
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; C106031:EWS-FLI fusion protein; C539965:NR0B1 protein, human; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS
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