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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression profiling of primary human retinoblastoma

ABSTRACT: Background Retinoblastoma is a pediatric eye cancer associated with RB1 loss or MYCN amplification (RB1+/+MYCNA). There are controversies concerning the existence of molecular subtypes within RB1-/- retinoblastoma. To test whether these molecular subtypes exist, we performed molecular profiling. Methods Genome-wide mRNA expression profiling was performed on 76 primary human retinoblastomas. Expression profiling was complemented by genome-wide DNA profiling and clinical, histopathological, and ex vivo drug sensitivity data. Findings RNA and DNA profiling identified major variability between retinoblastomas. While gene expression differences between RB1+/+MYCNA and RB1-/- tumors seemed more dichotomous, differences within the RB1-/- tumors were gradual. Tumors with high expression of a photoreceptor gene signature were highly differentiated, smaller in volume and diagnosed at younger age compared to tumors with low photoreceptor signature expression. Tumors with lower photoreceptor expression showed increased expression of genes involved in M-phase and mRNA and ribosome synthesis and increased frequencies of somatic copy number alterations. Interpretation Molecular, clinical and histopathological differences between RB1-/- tumors are best explained by tumor progression, reflected by a gradual loss of differentiation and photoreceptor expression signature. Since copy number alterations were more frequent in tumors with less photoreceptorness, genomic alterations might be drivers of tumor progression. Fresh frozen material from 76 primary human retinoblastoma samples were profiled with Affymetrix human genome u133 plus 2.0 PM microarray

ORGANISM(S): Homo sapiens

SUBMITTER: Irsan Kooi

PROVIDER: E-GEOD-59983 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Gene expression profiling of primary human retinoblastoma

Project description:Background Retinoblastoma is a pediatric eye cancer associated with RB1 loss or MYCN amplification (RB1+/+MYCNA). There are controversies concerning the existence of molecular subtypes within RB1-/- retinoblastoma. To test whether these molecular subtypes exist, we performed molecular profiling. Methods Genome-wide mRNA expression profiling was performed on 76 primary human retinoblastomas. Expression profiling was complemented by genome-wide DNA profiling and clinical, histopathological, and ex vivo drug sensitivity data. Findings RNA and DNA profiling identified major variability between retinoblastomas. While gene expression differences between RB1+/+MYCNA and RB1-/- tumors seemed more dichotomous, differences within the RB1-/- tumors were gradual. Tumors with high expression of a photoreceptor gene signature were highly differentiated, smaller in volume and diagnosed at younger age compared to tumors with low photoreceptor signature expression. Tumors with lower photoreceptor expression showed increased expression of genes involved in M-phase and mRNA and ribosome synthesis and increased frequencies of somatic copy number alterations. Interpretation Molecular, clinical and histopathological differences between RB1-/- tumors are best explained by tumor progression, reflected by a gradual loss of differentiation and photoreceptor expression signature. Since copy number alterations were more frequent in tumors with less photoreceptorness, genomic alterations might be drivers of tumor progression.

2015-07-01 | GSE59983 | GEO

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Affymetrix SNP array data for cone precursor derived retinoblastoma like samples

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Project description:Human embryonic stem cells (hESCs) provide a platform for understanding mechanisms underlying diseases and finding ways to treat them. Trilateral retinoblastoma (TRb) is a condition in which retinoblastoma, the most common congenital intraocular malignancy, is associated with an intracranial neural tumor. This mostly fatal disease is caused by biallelic inactivation of the retinoblastoma-1 (RB1) gene, transcribing pRB. Using CRISPR-Cas9 we generated RB1-null hESCs, an embryonic lethal condition. These cells display distinct gene expression patterns with alterations in pRB targets, and mitochondrial phenotypes similar to those of poorly differentiated retinoblastomas. RB1–/– hESC produce extremely large teratomas, with neural expansions similar to those of TRb tumors. Analysis of these tumors revealed a potentially novel role of pRB in ectoderm differentiation, acting through ZEB1. Lastly, RB1–/– cells are significantly sensitive to carboplatin, a chemotherapy used to treat TRb, suggesting our model can be used to screen novel treatments for the disease.

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Sequencing of Retinoblastoma

Project description:<p>Retinoblastoma is a pediatric cancer of the developing retina. All retinoblastomas are believed to initiate with biallelic inactivation of the RB1 gene. To identify subsequent genetic lesions in retinoblastoma, we performed whole genome sequencing of tumor and normal DNA of 4 children with retinoblastoma and one matched orthotopic xenograft. Both alleles of RB1 were inactivated in the tumor samples. 3 of the patients had sporadic retinoblastoma and one patient had inherited retinoblastoma. Overall, there were few single nucleotide changes in coding regions of the genome and some of the tumors had few chromosomal lesions. There were very few new genetic lesions in the xenograft compared to the primary tumor. These data suggest that the genome in retinoblastoma is more stable than previously believed and there are relatively few recurrent genetic lesions in known cancer pathways other than the RB1 pathway.</p>

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RB1 Gene Inactivation by Chromothripsis in Human Retinoblastoma

Project description:Retinoblastoma is a rare childhood cancer of the developing retina. Most retinoblastomas initiate with biallelic inactivation of the RB1 gene through diverse mechanisms including point mutations, nucleotide insertions, deletions, loss of heterozygosity and promoter hypermethylation. Recently, a novel mechanism of retinoblastoma initiation was proposed. Gallie and colleagues discovered that a small proportion of retinoblastomas lack RB1 mutations and had MYCN amplification [1]. In this study, we identified recurrent chromosomal, regional and focal genomic lesions in 94 primary retinoblastomas with their matched normal DNA using SNP 6.0 chips. We also analyzed the RB1 gene mutations and compared the mechanism of RB1 inactivation to the recurrent copy number variations in the retinoblastoma genome. In addition to the previously described focal amplification of MYCN and deletions in RB1 and BCOR, we also identified recurrent focal amplification of OTX2, a transcription factor required for retinal photoreceptor development. We identified 10 retinoblastomas in our cohort that lacked RB1 point mutations or indels. We performed whole genome sequencing on those 10 tumors and their corresponding germline DNA. In one of the tumors, the RB1 gene was unaltered, the MYCN gene was amplified and RB1 protein was expressed in the nuclei of the tumor cells. In addition, several tumors had complex patterns of structural variations and we identified 3 tumors with chromothripsis at the RB1 locus. This is the first report of chromothripsis as a mechanism for RB1 gene inactivation in cancer.

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Affymetrix SNP array data for cone precursor derived retinoblastoma like samples

2014-08-25 | GSE60720 | GEO

QUANTITATIVE PHOSPHOPROTEOMIC PROFILING OF PRIMARY RETINOBLASTOMA TUMORS

Project description:Retinoblastoma is a malignant tumor of the retina which most often occurs in children below 5 years of age with an incident rate of about 1 in 15,000 to 18,000 live births. Retinoblastoma is the first ever cancer that was reported to have a genetic basis. It occurs widely due to inactivating mutations in RB1 gene. Gene expression studies, copy number variation analysis, epigenetic profiling including miRNA and methylation of retinoblastoma has been carried to understand the disease mechanism and key players in the disease. Our group has earlier performed differential proteomics of retinoblastoma to identify proteins of therapeutic importance. However, there are no studies to understand the signalling mechanisms associated with retinoblastoma. Hence, global phosphoproteomics of retinoblastoma was carried out to identify signalling events associated with this cancer. Our study identified stress response proteins to be hyper phosphorylated which included H2AFX and sirtuin 1. In particular, Ser140 of H2AFX also known as gamma-H2AX was found to be hyperphosphorylated in retinoblastoma that indicated activation of DNA damage response pathways. We also observed activation of anti-apoptotic proteins in retinoblastoma compared to control. These observations showed activation of survival pathways and signalling networks activated in tumors.

2019-11-11 | PXD007228 | Pride

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