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- Carén, Helena, 1979, et al.
(författare)
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A cluster of genes located in 1p36 are down-regulated in neuroblastomas with poor prognosis, but not due to CpG island methylation.
- 2005
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Ingår i: Molecular cancer. - : Springer Science and Business Media LLC. - 1476-4598. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A common feature of neuroblastoma tumours are partial deletions of the short arm of chromosome 1 (1p-deletions). This is indicative of a neuroblastoma tumour suppressor gene being located in the region. Several groups including our have been studying candidate neuroblastoma genes in the region, but no gene/genes have yet been found that fulfil the criteria for being a neuroblastoma tumour suppressor. Since frequent mutations have not been detected, we have now analyzed the expression and promoter CpG island methylation status of the genes UBE4B, KIF1B, PGD, APITD1, DFFA and PEX14 in the 1p36.22 region in order to find an explanation for a possible down-regulation of this region. RESULTS: The current study shows that gene transcripts in high stage neuroblastoma tumours are significantly down-regulated compared to those in low stage tumours in the 1p36.22 region. CpG island methylation does not seem to be the mechanism of down-regulation for most of the genes tested, since no methylation was detected in the fragments analyzed. One exception is the CpG island of APITD1. Methylation of this gene is also seen in blood from control individuals and is therefore not believed to participate in tumour development. CONCLUSION: The genes UBE4B, KIF1B, PGD, APITD1, DFFA and PEX14 are down-regulated in high stage NB tumours, a feature that can not be explained by CpG island methylation.
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| 2. |
- Ejeskär, Katarina, 1969, et al.
(författare)
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Introduction of in vitro transcribed ENO1 mRNA into neuroblastoma cells induces cell death.
- 2005
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Ingår i: BMC cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Neuroblastoma is a solid tumour of childhood often with an unfavourable outcome. One common genetic feature in aggressive tumours is 1p-deletion.The alpha-enolase (ENO1) gene is located in chromosome region 1p36.2, within the common region of deletion in neuroblastoma. One alternative translated product of the ENO1 gene, known as MBP-1, acts as a negative regulator of the c-myc oncogene, making the ENO1 gene a candidate as a tumour suppressor gene. METHODS: Methods used in this study are transfection of cDNA-vectors and in vitro transcribed mRNA, cell growth assay, TUNEL-assay, real-time RT-PCR (TaqMan) for expression studies, genomic sequencing and DHPLC for mutation detection. RESULTS: Here we demonstrate that transfection of ENO1 cDNA into 1p-deleted neuroblastoma cell lines causes' reduced number of viable cells over time compared to a negative control and that it induces apoptosis. Interestingly, a similar but much stronger dose-dependent reduction of cell growth was observed by transfection of in vitro transcribed ENO1 mRNA into neuroblastoma cells. These effects could also be shown in non-neuroblastoma cells (293-cells), indicating ENO1 to have general tumour suppressor activity.Expression of ENO1 is detectable in primary neuroblastomas of all different stages and no difference in the level of expression can be detected between 1p-deleted and 1p-intact tumour samples. Although small numbers (11 primary neuroblastomas), there is some evidence that Stage 4 tumours has a lower level of ENO1-mRNA than Stage 2 tumours (p = 0.01). However, mutation screening of 44 primary neuroblastomas of all different stages, failed to detect any mutations. CONCLUSION: Our studies indicate that ENO1 has tumour suppressor activity and that high level of ENO1 expression has growth inhibitory effects.
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| 3. |
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| 4. |
- Krona, Cecilia, 1976, et al.
(författare)
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Analysis of neuroblastoma tumour progression; loss of PHOX2B on 4p13 and 17q gain are early events in neuroblastoma tumorigenesis
- 2008
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Ingår i: International Journal of Oncology. - 1019-6439. ; 32:3, s. 575-583
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Tidskriftsartikel (refereegranskat)abstract
- Neuroblastomas are biologically and clinically heterogeneous tumours that most often occur sporadically in children at median age 2. The PHOX2B gene is implicated in the development of the autonomic nervous system and has been found to be infrequently mutated in sporadic neuroblastoma tumours and in some patients with hereditary neuroblastoma. We have screened a selected series of 36 paediatric tumours with presumed genetic predisposition, 34 of them neuroblastomas, for mutations in PHOX2B. A constitutional heterozygous missense mutation was found in a boy who developed bilateral adrenal tumours and stage 4 disease during infancy. The second allele of the PHOX2B locus was lost in the tumour DNA. Histopathological evaluation of the tumours suggested growth of two primary tumours, one with diploid DNA content and the other with tetraploid DNA content, i.e. a case of neuroblastoma stage 4M (multifocal tumour). However, array CGH (comparative genomic hybridization) data performed on both tumour masses from the patient instead supported a model where a common malignant precursor gave rise to the diploid tumour and subsequently the tetraploid tumour have progressed from the common precursor or by metastasis from the diploid tumour with additional genetic changes. The whole genome dosage analysis showed that the remaining alleles of PHOX2B had been lost in both tumours together with a specific 17q gain pattern. The tetraploid tumour had these features together with additional whole chromosomal loss of chromosomes 3, 9, 14, and 15. Based on the data presented here we suggest that loss of PHOX2B and 17q gain are early events in neuroblastoma tumourigenesis. We also propose investigators to re-analyze the rare cases of multifocal neuroblastomas with the array CGH technique for better understanding of the origin of these tumours.
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| 5. |
- Krona, Cecilia, 1976
(författare)
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Identification and characterization of candidate genes for neuroblastoma development
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuroblastoma (NB) is the most common tumor during infancy. It arises from undifferentiated cells in the sympathetic nervous system and is characterized by both clinical and genetic heterogeneity. One of the features of NBs with unfavorable outcome is loss on distal chromosome 1p. The aim of this thesis was to identify genetic factors with relevance for NB tumorigenesis, with special emphasis on the tumor suppressor candidate region on chromosome 1p36.2. All known genes (UBE4B, KIF1B, PGD, CORT, DFFA and PEX14) in the hotspot NB tumor suppressor gene region on 1p36.22 were screened for mutations by capillary-based sequencing of DNA from a large series of NB tumors. The potential tumor suppressor properties of the genes ENO1, ICAT and CASP9, located close to this region, were also analyzed. A few mutations with predicted deleterious effects on protein function were found in the apoptotic regulator DFFA and in the UBE4B gene, which is involved in selective protein degradation. We were also able to show that expression of ENO1, DFFA, UBE4B and CASP9, critical for induction of the apoptotic cascade, is down-regulated in tumors with unfavorable outcome. We identified a novel gene, denoted APITD1, in 1p36.22; two alternative transcripts of this gene were abundantly expressed in normal adult and fetal tissues. Primary NB tumors showed either very weak or no measurable APITD1 expression and the lowest levels were detected in tumors with unfavorable outcome. The coding sequence of APITD1 was well-conserved in different species and no coding variations were found in primary NB tumors. Anti-proliferative and apoptotic effects were observed after over-expression of APITD1 and ENO1 in NB cell lines and in embryonal kidney- derived cells. A mutated ENO1 construct was used to show that the glycolytic enzyme α-enolase had as strong an effect on cell proliferation as the other translational product, MBP1, which is a negative regulator of the c-Myc oncogene. Biallelic inactivation of the transcription factor PHOX2B on chromosome 4p was found in a patient with multifocal NB, emphasizing the importance of early embryologic differentiation pathways in tumors of neural crest origin. A few rare mutations were found in genes with possible tumor suppressor functions. Several genes on 1p36.2 were also shown to be down-regulated in aggressive tumors. We therefore propose that the poor prognosis for NB patients with 1p deletions is a syngenic effect of mutations or transcriptional silencing of several genes in this region.
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