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

Santo, E. E.; Ebus, M. E.; Koster, J.; Schulte, J. H.; Lakeman, A.; van Sluis, P.; Vermeulen, J.; Gisselsson Nord, David LU ; Øra, Ingrid LU and Lindner, S., et al. (2012) In Oncogene 31(12). p.1571-1581
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... (More)
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. Oncogene (2012) 31, 1571-1581; doi:10.1038/onc.2011.344; published online 22 August 2011 (Less)
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keywords
MLL, 11q23, neuroblastoma, forkhead-box, FOXO, FOXR1
in
Oncogene
volume
31
issue
12
pages
1571 - 1581
publisher
Nature Publishing Group
external identifiers
  • wos:000302132000009
  • scopus:84860391821
ISSN
1476-5594
DOI
10.1038/onc.2011.344
language
English
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yes
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a2d7b9eb-cade-497a-a0f1-c69ddf370a81 (old id 2494829)
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2012-05-07 15:58:05
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2017-10-22 03:26:17
@article{a2d7b9eb-cade-497a-a0f1-c69ddf370a81,
  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. Oncogene (2012) 31, 1571-1581; doi:10.1038/onc.2011.344; published online 22 August 2011},
  author       = {Santo, E. E. and Ebus, M. E. and Koster, J. and Schulte, J. H. and Lakeman, A. and van Sluis, P. and Vermeulen, J. and Gisselsson Nord, David and Øra, Ingrid and Lindner, S. and Buckley, P. G. and Stallings, R. L. and Vandesompele, J. and Eggert, A. and Caron, H. N. and Versteeg, R. and Molenaar, J. J.},
  issn         = {1476-5594},
  keyword      = {MLL,11q23,neuroblastoma,forkhead-box,FOXO,FOXR1},
  language     = {eng},
  number       = {12},
  pages        = {1571--1581},
  publisher    = {Nature Publishing Group},
  series       = {Oncogene},
  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},
}