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Oncogenic activation of FOXR1 by 11q23 intrachromosomal deletion-fusions in neuroblastoma

(2012) ONCOGENE. 31(12). p.1571-1581
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Abstract
Neuroblastoma tumors frequently show loss of heterozygosity of chromosome 11q with a shortest region of overlap in the 11q23 region. These deletions are thought to cause inactivation of tumor suppressor genes leading to haploinsufficiency. Alternatively, micro-deletions could lead to gene fusion products that are tumor driving. To identify such events we analyzed a series of neuroblastomas by comparative genomic hybridization and single-nucleotide polymorphism arrays and integrated these data with Affymetrix mRNA profiling data with the bioinformatic tool R2 (http://r2.amc.nl). We identified three neuroblastoma samples with small interstitial deletions at 11q23, upstream of the forkhead-box R1 transcription factor (FOXR1). Genes at the proximal side of the deletion were fused to FOXR1, resulting in fusion transcripts of MLL-FOXR1 and PAFAH1B2-FOXR1. FOXR1 expression has only been detected in early embryogenesis. Affymetrix microarray analysis showed high FOXR1 mRNA expression exclusively in the neuroblastomas with micro-deletions and rare cases of other tumor types, including osteosarcoma cell line HOS. RNAi silencing of FOXR1 strongly inhibited proliferation of HOS cells and triggered apoptosis. Expression profiling of these cells and reporter assays suggested that FOXR1 is a negative regulator of fork-head box factor-mediated transcription. The neural crest stem cell line JoMa1 proliferates in culture conditional to activity of a MYC-ER transgene. Over-expression of the wild-type FOXR1 could functionally replace MYC and drive proliferation of JoMa1. We conclude that FOXR1 is recurrently activated in neuroblastoma by intrachromosomal deletion/fusion events, resulting in overexpression of fusion transcripts. Forkhead-box transcription factors have not been previously implicated in neuroblastoma pathogenesis. Furthermore, this is the first identification of intrachromosomal fusion genes in neuroblastoma.
Keywords
forkhead-box, neuroblastoma, MLL, FOXO, FOXR1, 11q23, FORKHEAD TRANSCRIPTION FACTOR, TUMOR-SUPPRESSOR GENE, ALVEOLAR RHABDOMYOSARCOMA, EXPRESSION PATTERNS, CELL-SURVIVAL, IN-SILICO, IDENTIFICATION, CANCER, COMMON

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Chicago
Santo, EE, ME Ebus, J Koster, JH Schulte, A Lakeman, P van Sluis, J Vermeulen, et al. 2012. “Oncogenic Activation of FOXR1 by 11q23 Intrachromosomal Deletion-fusions in Neuroblastoma.” Oncogene 31 (12): 1571–1581.
APA
Santo, E., Ebus, M., Koster, J., Schulte, J., Lakeman, A., van Sluis, P., Vermeulen, J., et al. (2012). Oncogenic activation of FOXR1 by 11q23 intrachromosomal deletion-fusions in neuroblastoma. ONCOGENE, 31(12), 1571–1581.
Vancouver
1.
Santo E, Ebus M, Koster J, Schulte J, Lakeman A, van Sluis P, et al. Oncogenic activation of FOXR1 by 11q23 intrachromosomal deletion-fusions in neuroblastoma. ONCOGENE. 2012;31(12):1571–81.
MLA
Santo, EE, ME Ebus, J Koster, et al. “Oncogenic Activation of FOXR1 by 11q23 Intrachromosomal Deletion-fusions in Neuroblastoma.” ONCOGENE 31.12 (2012): 1571–1581. Print.
@article{3171494,
  abstract     = {Neuroblastoma tumors frequently show loss of heterozygosity of chromosome 11q with a shortest region of overlap in the 11q23 region. These deletions are thought to cause inactivation of tumor suppressor genes leading to haploinsufficiency. Alternatively, micro-deletions could lead to gene fusion products that are tumor driving. To identify such events we analyzed a series of neuroblastomas by comparative genomic hybridization and single-nucleotide polymorphism arrays and integrated these data with Affymetrix mRNA profiling data with the bioinformatic tool R2 (http://r2.amc.nl). We identified three neuroblastoma samples with small interstitial deletions at 11q23, upstream of the forkhead-box R1 transcription factor (FOXR1). Genes at the proximal side of the deletion were fused to FOXR1, resulting in fusion transcripts of MLL-FOXR1 and PAFAH1B2-FOXR1. FOXR1 expression has only been detected in early embryogenesis. Affymetrix microarray analysis showed high FOXR1 mRNA expression exclusively in the neuroblastomas with micro-deletions and rare cases of other tumor types, including osteosarcoma cell line HOS. RNAi silencing of FOXR1 strongly inhibited proliferation of HOS cells and triggered apoptosis. Expression profiling of these cells and reporter assays suggested that FOXR1 is a negative regulator of fork-head box factor-mediated transcription. The neural crest stem cell line JoMa1 proliferates in culture conditional to activity of a MYC-ER transgene. Over-expression of the wild-type FOXR1 could functionally replace MYC and drive proliferation of JoMa1. We conclude that FOXR1 is recurrently activated in neuroblastoma by intrachromosomal deletion/fusion events, resulting in overexpression of fusion transcripts. Forkhead-box transcription factors have not been previously implicated in neuroblastoma pathogenesis. Furthermore, this is the first identification of intrachromosomal fusion genes in neuroblastoma.},
  author       = {Santo, EE and Ebus, ME and Koster, J and Schulte, JH and Lakeman, A and van Sluis, P and Vermeulen, J and Gisselsson, D and {\O}ra, I and Lindner, S and Buckley, PG and Stallings, RL and Vandesompele, Jo and Eggert, A and Caron, HN and Versteeg, R and Molenaar, JJ},
  issn         = {0950-9232},
  journal      = {ONCOGENE},
  keyword      = {forkhead-box,neuroblastoma,MLL,FOXO,FOXR1,11q23,FORKHEAD TRANSCRIPTION FACTOR,TUMOR-SUPPRESSOR GENE,ALVEOLAR RHABDOMYOSARCOMA,EXPRESSION PATTERNS,CELL-SURVIVAL,IN-SILICO,IDENTIFICATION,CANCER,COMMON},
  language     = {eng},
  number       = {12},
  pages        = {1571--1581},
  title        = {Oncogenic activation of FOXR1 by 11q23 intrachromosomal deletion-fusions in neuroblastoma},
  url          = {http://dx.doi.org/10.1038/onc.2011.344},
  volume       = {31},
  year         = {2012},
}

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