Expression and sequence analysis of candidates for the 1p36.31 tumor suppressor gene deleted in neuroblastomas

Okawa, Erin; Gotoh, Takahiro; Manne, Jayanthi; Igarashi, Jun; Fujita, Tomoyuki; Silverman, Karen A.; Xhao, H; Mossé, Yaël P.; White, Peter S.; Brodeur, Garrett M.

doi:10.1038/sj.onc.1210675

Cited by 88 publications

(100 citation statements)

References 34 publications

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“…Two genes of the apoptosis pathway, TNFRSF25 and CASP9, are located within the deleted region on 1p35.3-36.31, which is specific for RET/PTC-positive cases from adults. TNFRSF25 is also a candidate tumour suppressor in neuroblastomas (Okawa et al, 2008), whereas CASP9 deregulation has frequently been described in human cancers, for example in gastric carcinomas where it is reported that its activation is inhibited by phosphorylation through the MAP kinase pathway (Yoo et al, 2007). An interesting finding of this study is the deletion of RET because its activated form, RET/PTC, is known as a marker of PTC.…”

Section: Array Cgh On Ptc K Unger Et Almentioning

confidence: 71%

Array CGH demonstrates characteristic aberration signatures in human papillary thyroid carcinomas governed by RET/PTC

et al. 2008

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The aim of this study is to investigate additional genetic alterations in papillary thyroid carcinomas (PTCs) with known RET/PTC rearrangements. We applied arraybased comparative genomic hybridization (array CGH) to 33 PTC (20 PTC from adults, 13 post-Chernobyl PTC from children) with known RET/PTC status. Principal component analysis and hierarchical cluster analysis identified cases with similar aberration patterns. Significant deviations between tumour-groups were obtained by statistical testing (Fisher's exact test in combination with Benjamini-Hochberg FDR-controlling procedure). FISH analysis on FFPE sections was applied to validate the array CGH data. Deletions were found more frequently in RET/PTC-positive and RET/PTC-negative tumours than amplifications. Specific aberration signatures were identified that discriminated between RET/PTC-positive and RET/PTC-negative cases (aberrations on chromosomes 1p, 3q, 4p, 7p, 9p/q, 10q, 12q, 13q and 21q). In addition, childhood and adult RET/PTC-positive cases differ significantly for a deletion on the distal part of chromosome 1p. There are additional alterations in RET/PTC-positive tumours, which may act as modifiers of RET activation. In contrast, alterations in RET/ PTC-negative tumours indicate alternative routes of tumour development. The data presented serve as a starting point for further studies on gene expression and function of genes identified in this study.

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Section: Array Cgh On Ptc K Unger Et Almentioning

confidence: 71%

Array CGH demonstrates characteristic aberration signatures in human papillary thyroid carcinomas governed by RET/PTC

et al. 2008

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“…The recent description in this region of CHD5 as a new tumor suppressor in human cancer threw light on this issue. 40,55 CHD5 appeared as a target shared for miR-1201, miR-1202 and miR-1203. Interestingly, PRDM16, Wnt3 and Hes genes are predicted targets that map into the same region of human chromosome 1p36 and also appear to constitute shared targets for these same novel miRNA (Table 4 and Supplemental Table 1).…”

Section: Discussionmentioning

confidence: 99%

Small RNAs analysis in CLL reveals a deregulation of miRNA expression and novel miRNA candidates of putative relevance in CLL pathogenesis

et al. 2007

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UruguayMicroRNAs (miRNAs) are a novel class of small noncoding RNA molecules that regulate gene expression by inducing degradation or translational inhibition of target mRNAs. There are more than 500 miRNA genes reported in the human genome, constituting one of the largest classes of regulatory genes. Increasing experimental evidence supports the idea of aberrant miRNA expression in cancer pathogenesis. We analyzed the pattern of miRNA expression in chronic lymphocytic leukemia (CLL) cells and our results showed a global reduction in miRNA expression levels in CLL cells associated to a consistent underexpression of miR-181a, let-7a and miR-30d. We observed overexpression of miR-155 and a set of five miRNAs that are differentially expressed between patients with different clinical outcomes. Five novel miRNA candidates cloned from leukemic cells are reported. Surprisingly, predicted mRNA targets for these novel miRNA revealed a high proportion of targets located in a small region of chromosome 1, which is frequently altered in human cancer. Additionally, several targets were shared by at least two of miRNA candidates. Predicted targets included several genes recently described as tumor suppressors. These data could afford new avenues for exploring innovative pathways in CLL biology and therapy.

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“…101 Expression of CHD5 is very low or absent in neuroblastoma cell lines and is inversely correlated with 1p deletion, MYCN amplification, advanced clinical stage, unfavorable histology, and poor eventfree and overall survival in neuroblastoma tumors. [99][100][101] Homozygous deletion and mutational inactivation of CHD5 are infrequent events, 99 but it has been shown that the remaining CHD5 allele in neuroblastoma cells with heterozygous 1p deletion may be transcriptionally silenced by promoter methylation. 100 Reintroduction of CHD5 in such neuroblastoma cells with 1p deletion and epigenetic CHD5 silencing significantly reduced clonogenicity and in vivo tumorigenicity, validating CHD5 as a bona fide tumor suppressor gene.…”

Section: Transactivation Of Mdm2 Expression By Mycnmentioning

confidence: 99%

“…98 The actual target of this deletion has remained elusive for a long time, but detailed analysis of the different genes located in the smallest region of deletion at 1p36.31 has recently identified CHD5 as the strongest candidate tumor suppressor gene. 99,100 CHD5 encodes a protein with chromatin-organizing modulator (chromo), helicase, and DNA-binding motifs that is preferentially expressed in the nervous system and the adrenal gland. 101 Expression of CHD5 is very low or absent in neuroblastoma cell lines and is inversely correlated with 1p deletion, MYCN amplification, advanced clinical stage, unfavorable histology, and poor eventfree and overall survival in neuroblastoma tumors.…”

Section: Transactivation Of Mdm2 Expression By Mycnmentioning

confidence: 99%

Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14ARF-MDM2-p53 axis

et al. 2009

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A primary failsafe program against unrestrained proliferation and oncogenesis is provided by the p53 tumor suppressor protein, inactivation of which is considered as a hallmark of cancer. Intriguingly, mutations of the TP53 gene are rarely encountered in neuroblastoma tumors, suggesting that alternative p53-inactivating lesions account for escape from p53 control in this childhood malignancy. Several recent studies have shed light on the mechanisms by which neuroblastoma cells circumvent the p53-driven antitumor barrier. We review here these mechanisms for evasion of p53-mediated growth control and conclude that deregulation of the p14 ARF -MDM2-p53 axis seems to be the principal mode of p53 inactivation in neuroblastoma, opening new perspectives for targeted therapeutic intervention. The p53 tumor surveillance network constitutes the core defense mechanism of the cell against loss of genomic integrity and malignant transformation. Evasion of p53 activity is, therefore, a prerequisite for tumor cells to survive and thrive, and this is attainable either through mutation of the TP53 gene or through defects in the molecular components that govern or execute the various aspects of the p53 response. Elucidation of the mechanisms by which tumor cells override the p53-orchestrated failsafe program is not only important to gain insight into the ontogenesis of a tumor, but may also point to preferable modes of therapeutic intervention.A striking feature of the childhood cancer neuroblastoma is the low frequency (o2%) of TP53 mutations at diagnosis. 1 There is considerable evidence that TP53 mutations may be acquired during chemotherapy and malignant progression of neuroblastoma. 1-4 Accordingly, an increased frequency of TP53 mutations is observed in multidrug-resistant neuroblastoma cell lines and in neuroblastoma cell lines established at relapse, but even in this context, the majority of cell lines remain characterized by a wild-type TP53 gene. 5,6 Furthermore, many studies indicate that the p53 signal transduction pathway is intrinsically intact in neuroblastoma, 1,4,7-9 suggesting that circumvention of the p53 barrier in this tumor entity relies primarily on an inappropriately increased activity of inhibitors of p53 signaling or, alternatively, on a loss of positive regulators of p53 activity. This review summarizes our current understanding of the mechanisms by which neuroblastoma cells escape from p53-mediated tumor surveillance and positions deregulation of the p14 ARF -MDM2-p53 axis as a central switch for p53 inactivation in neuroblastoma.The p14 ARF -MDM2-p53 Axis and Lesions at the MDM2 and CDKN2A (p16 INK4a /p14 ARF ) Loci in NeuroblastomaThe MDM2 oncoprotein, a human homolog of the 'mouse double minute 2' gene product that was originally identified in a spontaneously transformed mouse cell line with double minute chromosomes, 10 is a critical negative regulator of p53 stability and activity. It has been well established that p53 and MDM2 mutually control their cellular levels and form a tight autoregulatory...

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Expression and sequence analysis of candidates for the 1p36.31 tumor suppressor gene deleted in neuroblastomas

Cited by 88 publications

References 34 publications

Array CGH demonstrates characteristic aberration signatures in human papillary thyroid carcinomas governed by RET/PTC

Array CGH demonstrates characteristic aberration signatures in human papillary thyroid carcinomas governed by RET/PTC

Small RNAs analysis in CLL reveals a deregulation of miRNA expression and novel miRNA candidates of putative relevance in CLL pathogenesis

Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14ARF-MDM2-p53 axis

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