Biological characteristics of neuroblastoma with partial deletion in the short arm of chromosome 1

Hiyama, Eiso; Hiyama, Keiko; Ohtsu, Kazuhiro; Yamaoka, Hiroaki; Fukuba, Ikuko; Matsuura, Yuichiro; Yokoyama, Takashi

doi:10.1002/1096-911x(20010101)36:1<67::aid-mpo1017>3.0.co;2-s

Cited by 20 publications

(7 citation statements)

References 27 publications

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“…In human neuroblastomas, a high percentage (Ϸ28-47%) contain deletions of chromosome 1p (28)(29)(30)(31). Analyses of such chromosome deletions suggest that there may be tumor-suppressor gene(s) in the region 1p36.1-1p36.3, which contains both DFF40͞CAD and DFF45͞ICAD (29,(31)(32)(33)(34). In agreement with this finding is a report showing the homozygous deletion of DFF45 in neuroblastoma cell lines (7).…”

Section: Discussionmentioning

confidence: 99%

A unique role of the DNA fragmentation factor in maintaining genomic stability

Yan

Wang

Peng

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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DNA fragmentation is a hallmark of apoptosis (programmed cell death). However, the biological function of apoptotic DNA fragmentation remains unclear. Here, we show that DNA fragmentation factor plays an important role for maintaining genomic stability. Inhibition or loss of the DNA fragmentation factor (DFF)͞ caspase-activated DNase (CAD), whose nuclease activity is responsible for digesting genomic DNA during apoptosis, led to significant increases in spontaneous or induced gene mutations, gene amplifications, and chromosomal instability in primary mouse cells and transformed human cell lines. The mechanism underlying genetic instability in DFF͞CAD-deficient cells, at least in part, involves a small but significant elevation in the survival of cells exposed to ionizing radiation, suggesting that apoptotic DNA fragmentation factor contributes to genomic stability by ensuring the removal of cells that have suffered DNA damage. In support of this hypothesis are the observations of increased cellular transformation of mouse embryonic cells from the DFF͞CAD-null mice and significantly enhanced susceptibility to radiation-induced carcinogenesis in these mice. These data, in combination with published reports on the existence of tumor-specific gene mutations͞dele-tions in the DFF͞CAD genes in human cancer samples, suggest that apoptotic DNA fragmentation factor is required for the maintenance of genetic stability and may play a role in tumor suppression.NA fragmentation is a hallmark of apoptosis (1, 2). It is now recognized that apoptotic DNA fragmentation is carried out by a heterodimeric protein complex called DNA fragmentation factor (DFF) (3, 4) or caspase-activated DNase (CAD) (5, 6). DFF is a heterodimeric protein complex composed of two subunits, DFF40͞CAD and DFF45͞inhibitor (I)CAD (3). DFF45͞ICAD is an inhibitor as well as a chaperone of DFF40͞CAD that ensures its proper folding. Expression of DFF40͞CAD in various systems in the absence of coexpressed DFF45 results in generation of DFF40-inactive aggregates. Under normal circumstances, DFF40͞CAD is complexed with DFF45͞ICAD, so its DNase activity is inhibited (3-5). When apoptosis is initiated, the activated caspase cleaves DFF45͞ICAD, and DFF40͞CAD is released into the nucleus to carry out DNA fragmentation.Recently, it was discovered that the genes encoding the nuclease that are responsible for the fragmentation of DNA during apoptosis, DFF40͞CAD and DFF45͞ICAD, are aberrantly expressed in many tumor types. In addition, the abnormalities in this gene are associated with poor prognosis in cancer patients (7-9). Most significantly, tumor-specific DFF45 gene mutations or deletions were identified in human germ cell tumors and neuroblastoma tumors from patients (10, 11), indicating the involvement of this gene in tumor development.The present study was initiated to explore the potential relationship between apoptotic DNA fragmentation and tumor development. We reasoned that the process involved in the destruction of genomic DNA might have a direct effect on g...

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Section: Discussionmentioning

confidence: 99%

A unique role of the DNA fragmentation factor in maintaining genomic stability

Yan

Wang

Peng

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…The CDKN2C (INK4C/p18) gene is located at 1p32, which is outside the smallest region of overlap (SRO) for 1p deletions in this study. Still this region is frequently deleted in neuroblastoma, and the 1p32 region has been suggested to play a role in neuroblastoma development (Hiyama et al, 2001). In our cohort of neuroblastoma, loss of 1p32 correlated with decreased CDKN2C expression (P ¼ 0.03, t-test), suggesting that copy number defects add to the decreased expression of CDKN2C.…”

Section: Cell Cycle Genes In Neuroblastomamentioning

confidence: 99%

Copy number defects of G1‐Cell cycle genes in neuroblastoma are frequent and correlate with high expression of E2F target genes and a poor prognosis

Molenaar

Koster

Ebus

et al. 2011

Genes Chromosomes & Cancer

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The tightly controlled network of cell cycle genes consists of a core of cyclin dependent kinases (CDKs) that are activated by periodically expressed cyclins. The activity of the cyclin-CDK complexes is regulated by cyclin dependent kinase inhibitors (CDKIs) and multiple signal transduction routes that converge on the cell cycle. Neuroblastoma are pediatric tumors that belong to the group of small round blue cell tumors, characterized by a fast proliferation. Here, we present high throughput analyses of cell cycle regulating genes in neuroblastoma. We analyzed a series of 82 neuroblastomas by comparative genomic hybridization arrays, single nucleotide polymorphism arrays, and Affymetrix expression arrays and analyzed the datasets in parallel with the R2 bioinformatic tool (http://r2.amc.nl). About 30% of the tumors had genomic amplifications, gains, or losses with shortest regions of overlap that suggested implication of a series of G1 cell cycle regulating genes. CCND1 (cyclin D1) and CDK4 were amplified or gained and the chromosomal regions containing the CDKN2 (INK4) group of CDKIs were frequently deleted. Cluster analysis showed that tumors with genomic aberrations in G1 regulating genes over-expressed E2F target genes, which regulate S and G2/M phase progression. These tumors have a poor prognosis. Our findings suggest that pharmacological inhibition of cell cycle genes might bear therapeutic promises for patients with high risk neuroblastoma.

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“…Upon studying neuroblastoma patient samples, Hiyama et al proposed the presence of a neuroblastoma tumour suppressor gene on Chromosome 1 loci, deletion of which links to aggressiveness of the tumour (Hiyama et al, ). Fong et al also observed that loss of heterozygosity in the Chromosome 1 short arm leads to aggressive neuroblastomas (Fong et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…During this process, one of the transfections resulted in development of a line that showed full trisomy of Chromosome 1 and a deletion of small fragment q23 to qter of Chromosome 11. As the sample was collected after full term delivery of the baby, the abnormality is expected to have originated either during (Hiyama et al, 2001). Fong et al also observed that loss of heterozygosity in the Chromosome 1 short arm leads to aggressive neuroblastomas (Fong et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Improved neural differentiation of normal and abnormal induced pluripotent stem cell lines in the presence of valproic acid

Fernandes

Vinnakota

Kumar

et al. 2019

J Tissue Eng Regen Med

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During the generation of induced pluripotent stem cell (iPSC) lines from cord blood CD34+ cells, a line having complete trisomy of Chromosome 1 and deletion of q23 to qTer of Chromosome 11 was accidentally developed in our lab. The abnormality was consistently detected even at higher passages. These chromosomal anomalies are known to manifest neurological developmental defects. In order to examine if such defects occur during in vitro differentiation of the cell line, we set up a protocol for neural differentiation. Valproic acid (VPA) was earlier reported by us to enhance neural differentiation of placental mesenchymal stem cells. Here, we induced normal and abnormal iPSC lines to neural lineage with/without VPA. Neural differentiation was observed in all four sets, but for both the iPSCs lines, VPA sets performed better. The characteristics tested were morphology, neural filament length, detection of neural markers, and electrophysiology. In summary, the karyotypically abnormal line exhibited efficient neural differentiation. This iPSC line may serve as a useful tool to study abnormalities associated with trisomy 1 and deletion of q23 to qTer of Chromosome 11.

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Biological characteristics of neuroblastoma with partial deletion in the short arm of chromosome 1

Cited by 20 publications

References 27 publications

A unique role of the DNA fragmentation factor in maintaining genomic stability

A unique role of the DNA fragmentation factor in maintaining genomic stability

Copy number defects of G1‐Cell cycle genes in neuroblastoma are frequent and correlate with high expression of E2F target genes and a poor prognosis

Improved neural differentiation of normal and abnormal induced pluripotent stem cell lines in the presence of valproic acid

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