Novel genomic imbalances in embryonal rhabdomyosarcoma revealed by comparative genomic hybridization and fluorescence in situ hybridization: An Intergroup Rhabdomyosarcoma Study

Bridge, Julia A.; Liu, Jian; Weibolt, Vines; Baker, K. Scott; Perry, Deborah; Kruger, Robert P.; Qualman, Stephen J.; Barr, Frederic G.; Sorensen, Poul H.; Triche, Timothy J.; Suijkerbuijk, Ron F.

doi:10.1002/(sici)1098-2264(200004)27:4<337::aid-gcc1>3.0.co;2-1

Cited by 143 publications

(116 citation statements)

References 22 publications

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“…The PI3 kinases are generally considered to function as oncogenes. Although, our data could not find any indications of PIK3CD acting as an oncogene in NB based on the following aspects: (a) PIK3CD is located in a chromosomal region where LOH is common in NB as well as in other paediatric tumours (Grundy et al, 1994;Benn et al, 2000;Bridge et al, 2000), (b) gene expression studies show a downregulation of transcripts in high-stage NB compared to low-stage (consistent with findings of an expression profiling of selected genes of chromosome region 1p35 -36 reported by Janoueix- Lerosey et al, 2004), (c) 5-Aza-dC and TSA studies indicate that PIK3CD could be influenced by epigenetic regulation in NB, (d) putative mutations have been identified. One could speculate that the mutations identified are gain-of-function mutations that would support the concept that the PIK3CD gene could act as an oncogene in NB.…”

Section: Discussionsupporting

confidence: 86%

Genetic and epigenetic changes in the common 1p36 deletion in neuroblastoma tumours

et al. 2007

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Chromosome 1p is frequently deleted in neuroblastoma (NB) tumours. The commonly deleted region has been narrowed down by loss of heterozygosity studies undertaken by different groups. Based on earlier mapping data, we have focused on a region on 1p36 (chr1: 7 765 595 -11 019 814) and performed an analysis of 30 genes by exploring features such as epigenetic regulation, that is DNA methylation and histone deacetylation, mutations at the DNA level and mRNA expression. Treatment of NB cell lines with the histone deacetylase inhibitor trichostatin A led to increased gene transcription of four of the 30 genes, ERRFI1 (MIG-6), PIK3CD, RBP7 (CRBPIV) and CASZ1, indicating that these genes could be affected by epigenetic downregulation in NBs. Two patients with nonsynonymous mutations in the PIK3CD gene were detected. One patient harboured three variations in the same exon, and p.R188W. The other patient had the variation p.M655I. In addition, synonymous variations and one variation in an intronic sequence were also found. The mRNA expression of this gene is downregulated in unfavourable, compared to favourable, NBs. One nonsynonymous mutation was also identified in the ERRFI1 gene, p.N343S, and one synonymous. None of the variations above were found in healthy control individuals. In conclusion, of the 30 genes analysed, the PIK3CD gene stands out as one of the most interesting for further studies of NB development and progression.

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Section: Discussionsupporting

confidence: 86%

Genetic and epigenetic changes in the common 1p36 deletion in neuroblastoma tumours

et al. 2007

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“…In fact, the endogenous level of PAX3-FKHR in RH30, an ARMS cell line, is much higher than the level tolerated by the immortalized murine cells, suggesting that features within these ARMS cells attenuate the toxic effects and permit the cells to tolerate high level expression of PAX3-FKHR. In our search for candidate collaborating events, others and we have found that gene amplification occurs frequently in ARMS but not ERMS cells (Bridge et al, 2000(Bridge et al, , 2002. For example, the most frequently amplified chromosomal regions are 2p24 (involving MYCN) and 12q13-15 (involving MDM2 and CDK4) (Berner et al, 1996).…”

Section: Collaboration Among Two or More Oncogenes Or Tumor Suppressomentioning

confidence: 87%

Analysis of the transforming and growth suppressive activities of the PAX3-FKHR oncoprotein

Xia

Barr

2004

Oncogene

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The 2;13 chromosomal translocation occurs in most cases of the cancer alveolar rhabdomyosarcoma (ARMS), and juxtaposes the genes encoding the PAX3 and FKHR transcription factors. The resulting chimeric protein PAX3-FKHR is a potent transcriptional activator, and is hypothesized to function as a dominant acting oncogene. To investigate its biological function, PAX3-FKHR was transduced into three immortalized murine cell lines in either a constitutive or inducible manner. These cells only tolerate expression of low PAX3-FKHR levels, which is sufficient for transformation in NIH3T3 cells. In contrast, higher PAX3-FKHR levels, which are comparable to the endogenous level expressed in ARMS cells, result in growth suppression. To determine as to which PAX3 functional domains are needed for growth suppression and transformation, inactivating mutations were introduced into the paired box and homeodomain of PAX3-FKHR. In these experiments, the homeodomain is necessary for transformation, but not growth suppression; whereas the paired box is not required for transformation but mediates growth suppression. In summary, our findings demonstrate that the transforming and growth suppressive activities of PAX3-FKHR are dominant at different activity levels and are mediated by distinct functional domains. These findings are consistent with the hypothesis that distinct expression pathways are operative in these opposing phenotypic end points.

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“…Alterations at the PTCH locus have also been identified in sporadic cases of tumors associated with the syndrome (for review see (Hahn et al, 1999)). In sporadic RMS, genomic loss of the PTCH locus on 9q22 has been identified in 30% of cases (Bridge et al, 2000). Interestingly, a high frequency of RMS is also observed in a mouse model for Ptch-deficiency (Goodrich et al, 1997;Hahn et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Analysis of thePTCH coding region in human rhabdomyosarcoma

et al. 2002

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Inherited mutations of the human tumor suppressor gene Patched (PTCH) lead to an autosomal dominant disorder known as Nevoid Basal Cell Carcinoma Syndrome (NBCCS).The syndrome is characterized by a combination of developmental abnormalities and a predisposition to tumor formation. Tumors in patients with NBCCS include basal cell carcinoma, medulloblastoma, fibroma and rhabdomyosarcoma (RMS). RMS are also present in 15 % of mice haplodeficient for Ptch. To investigate whether mutations in PTCH are a general feature in rhabdomyosarcomagenesis we sequenced the protein-coding region in sporadic human cases of these tumors. For this purpose we first determined the distribution and frequency of polymorphisms in 23 exons of PTCH in 48 healthy caucasians. Ten new polymorphisms were identified (IVS11 + 15-17del AAA; IVS14 + 25T>C; 2485G>A; IVS15 + 9G>C; IVS17 + 21A>G; 3033T>C; 3149T>C; 3387T>C; 3617G>A; 4080C>T). Next, the PTCH coding region in 14 RMS was sequenced. Whereas one case with LOH at the PTCH locus was detected, none of the cases showed nonsense or missense mutations in the coding region of PTCH. These data do not support the existence of frequent mutations in the protein-coding region of PTCH in RMS.

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Novel genomic imbalances in embryonal rhabdomyosarcoma revealed by comparative genomic hybridization and fluorescence in situ hybridization: An Intergroup Rhabdomyosarcoma Study

Cited by 143 publications

References 22 publications

Genetic and epigenetic changes in the common 1p36 deletion in neuroblastoma tumours

Genetic and epigenetic changes in the common 1p36 deletion in neuroblastoma tumours

Analysis of the transforming and growth suppressive activities of the PAX3-FKHR oncoprotein

Analysis of thePTCH coding region in human rhabdomyosarcoma

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