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No evidence for involvement of SDHD in neuroblastoma pathogenesis

Katleen De Preter UGent, Jo Vandesompele UGent, Jasmien Hoebeeck UGent, Caroline Vandenbroecke, Joél Smet UGent, Annick Nuyts, Genevieve Laureys UGent, Valérie Combaret, Nadine Van Roy UGent and Frank Roels UGent, et al. (2004) BMC CANCER. 4.
abstract
Background: Deletions in the long arm of chromosome 11 are observed in a subgroup of advanced stage neuroblastomas with poor outcome. The deleted region harbours the tumour suppressor gene SDHD that is frequently mutated in paraganglioma and pheochromocytoma, which are, like neuroblastoma, tumours originating from the neural crest. In this study, we sought for evidence for involvement of SDHD in neuroblastoma. Methods: SDHD was investigated on the genome, transcriptome and proteome level using mutation screening, methylation specific PCR, real-time quantitative PCR based homozygous deletion screening and mRNA expression profiling, immunoblotting, functional protein analysis and ultrastructural imaging of the mitochondria. Results: Analysis at the genomic level of 67 tumour samples and 37 cell lines revealed at least 2 bona-fide mutations in cell lines without allelic loss at 11q23: a 4bp-deletion causing skip of exon 3 resulting in a premature stop codon in cell line N206, and a Y93C mutation in cell line NMB located in a region affected by germline SDHD mutations causing hereditary paraganglioma. No evidence for hypermethylation of the SDHD promotor region was observed, nor could we detect homozygous deletions. Interestingly, SDHD mRNA expression was significantly reduced in SDHD mutated cell lines and cell lines with 11q allelic loss as compared to both cell lines without 11q allelic loss and normal foetal neuroblast cells. However, protein analyses and assessment of mitochondrial morphology presently do not provide clues as to the possible effect of reduced SDHD expression on the neuroblastoma tumour phenotype. Conclusions: Our study provides no indications for 2-hit involvement of SDHD in the pathogenesis of neuroblastoma. Also, although a haplo-insufficient mechanism for SDHD involvement in advanced stage neuroblastoma could be considered, the present data do not provide consistent evidence for this hypothesis.
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author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
COMPARATIVE GENOMIC HYBRIDIZATION, ELECTRON-MICROSCOPY, NECK PARAGANGLIOMAS, HEREDITARY PARAGANGLIOMA, OXIDATIVE-PHOSPHORYLATION, CELL-LINES, COMPLEX-II GENE, GERM-LINE MUTATIONS, MITOCHONDRIAL RESPIRATORY-CHAIN, SUCCINATE-UBIQUINONE OXIDOREDUCTASE
journal title
BMC CANCER
BMC Cancer
volume
4
article_number
55
pages
15 pages
Web of Science type
Article
Web of Science id
000223864600002
JCR category
ONCOLOGY
JCR impact factor
2.29 (2004)
JCR rank
60/120 (2004)
JCR quartile
2 (2004)
ISSN
1471-2407
DOI
10.1186/1471-2407-4-55
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
326712
handle
http://hdl.handle.net/1854/LU-326712
date created
2006-02-21 15:54:00
date last changed
2015-06-17 10:33:15
@article{326712,
  abstract     = {Background: Deletions in the long arm of chromosome 11 are observed in a subgroup of advanced stage neuroblastomas with poor outcome. The deleted region harbours the tumour suppressor gene SDHD that is frequently mutated in paraganglioma and pheochromocytoma, which are, like neuroblastoma, tumours originating from the neural crest. In this study, we sought for evidence for involvement of SDHD in neuroblastoma.
Methods: SDHD was investigated on the genome, transcriptome and proteome level using mutation screening, methylation specific PCR, real-time quantitative PCR based homozygous deletion screening and mRNA expression profiling, immunoblotting, functional protein analysis and ultrastructural imaging of the mitochondria.
Results: Analysis at the genomic level of 67 tumour samples and 37 cell lines revealed at least 2 bona-fide mutations in cell lines without allelic loss at 11q23: a 4bp-deletion causing skip of exon 3 resulting in a premature stop codon in cell line N206, and a Y93C mutation in cell line NMB located in a region affected by germline SDHD mutations causing hereditary paraganglioma. No evidence for hypermethylation of the SDHD promotor region was observed, nor could we detect homozygous deletions. Interestingly, SDHD mRNA expression was significantly reduced in SDHD mutated cell lines and cell lines with 11q allelic loss as compared to both cell lines without 11q allelic loss and normal foetal neuroblast cells. However, protein analyses and assessment of mitochondrial morphology presently do not provide clues as to the possible effect of reduced SDHD expression on the neuroblastoma tumour phenotype.
Conclusions: Our study provides no indications for 2-hit involvement of SDHD in the pathogenesis of neuroblastoma. Also, although a haplo-insufficient mechanism for SDHD involvement in advanced stage neuroblastoma could be considered, the present data do not provide consistent evidence for this hypothesis.},
  articleno    = {55},
  author       = {De Preter, Katleen and Vandesompele, Jo and Hoebeeck, Jasmien and Vandenbroecke, Caroline and Smet, Jo{\'e}l and Nuyts, Annick and Laureys, Genevieve and Combaret, Val{\'e}rie and Van Roy, Nadine and Roels, Frank and Van Coster, Rudy and Praet, Marleen and De Paepe, Anne and Speleman, Franki},
  issn         = {1471-2407},
  journal      = {BMC CANCER},
  keyword      = {COMPARATIVE GENOMIC HYBRIDIZATION,ELECTRON-MICROSCOPY,NECK PARAGANGLIOMAS,HEREDITARY PARAGANGLIOMA,OXIDATIVE-PHOSPHORYLATION,CELL-LINES,COMPLEX-II GENE,GERM-LINE MUTATIONS,MITOCHONDRIAL RESPIRATORY-CHAIN,SUCCINATE-UBIQUINONE OXIDOREDUCTASE},
  language     = {eng},
  pages        = {15},
  title        = {No evidence for involvement of SDHD in neuroblastoma pathogenesis},
  url          = {http://dx.doi.org/10.1186/1471-2407-4-55},
  volume       = {4},
  year         = {2004},
}

Chicago
De Preter, Katleen, Jo Vandesompele, Jasmien Hoebeeck, Caroline Vandenbroecke, Joél Smet, Annick Nuyts, Genevieve Laureys, et al. 2004. “No Evidence for Involvement of SDHD in Neuroblastoma Pathogenesis.” Bmc Cancer 4.
APA
De Preter, K., Vandesompele, J., Hoebeeck, J., Vandenbroecke, C., Smet, J., Nuyts, A., Laureys, G., et al. (2004). No evidence for involvement of SDHD in neuroblastoma pathogenesis. BMC CANCER, 4.
Vancouver
1.
De Preter K, Vandesompele J, Hoebeeck J, Vandenbroecke C, Smet J, Nuyts A, et al. No evidence for involvement of SDHD in neuroblastoma pathogenesis. BMC CANCER. 2004;4.
MLA
De Preter, Katleen, Jo Vandesompele, Jasmien Hoebeeck, et al. “No Evidence for Involvement of SDHD in Neuroblastoma Pathogenesis.” BMC CANCER 4 (2004): n. pag. Print.