Differential expression of MEN2 versus VHL human Pheochromocytomas
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE12642 | GEO | 2008/09/15
SECONDARY ACCESSION(S): PRJNA112827
REPOSITORIES: GEO
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Project description:This study utilized oligonucleotide microarrays to examine gene expression profiles in pheochromocytomas from 23 patients; 11 VHL tumors and 12 MEN2 tumors. RNA was extracted and linearly amplified once, then dye-labeled and co-hybridized to a microarray with over 34,000 oligos representing more than 25,000 unique human genes. In validation of our strategy, many genes known to have elevated expression in MEN2 tumors (e.g., CALM1, CHGB, CABP1and NPY) and several genes known to be specific to VHL (e.g., AQP1) were independently identified by this approach. In addition to known genes, our method has identified several hundred of previously uncharacterized genes that are enriched in the MEN2 or VHL tumors. A 34k expression arrays were generated by printing Oligo nucleotides from the Qiagen HV3 set onto epoxy coated slides (Corning, Inc). Total RNA from pheochrmocytoma tumors or normal adrenals was amplified using an Ambion kit (Cat#1753), labeled with Cy5 and cy3 dyes respectively and hybridized overnight to the oligo chip in a MAUI chamber.
2008-09-15 | E-GEOD-12642 | biostudies-arrayexpress
Project description:Pheochromocytomas are neural crest-derived tumors that arise from inherited or sporadic mutations in at least six independent genes: RET, VHL, NF1, and subunits B, C and D of succinate dehydrogenase (SDH). The proteins encoded by these multiple genes regulate distinct functions. To identify molecular interactions between the distinct pathways we performed expression profiling of a large cohort of pheochromocytomas. We show here a functional link between tumors with VHL mutations and those with disruption of the genes encoding for succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD). A transcription profile of reduced oxidoreductase is detected in all three of these tumor types, together with an angiogenesis/hypoxia profile typical of VHL dysfunction. The oxidoreductase defect, not previously detected in VHL-null tumors, is explained by suppression of the SDHB protein, a component of mitochondrial complex II. The decrease in SDHB is also noted in tumors with SDHD mutations. Gain-of-function and loss-of-function analyses show that the link between hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1?. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1? activity in tumors. Keywords: disease state analysis: Primary sporadic and hereditary pheochromocytomas and paragangliomas
2005-08-12 | GSE2841 | GEO
Project description:Pheochromocytomas are neural crest-derived tumors that arise from inherited or sporadic mutations in at least six independent genes: RET, VHL, NF1, and subunits B, C and D of succinate dehydrogenase (SDH). The proteins encoded by these multiple genes regulate distinct functions. To identify molecular interactions between the distinct pathways we performed expression profiling of a large cohort of pheochromocytomas. We show here a functional link between tumors with VHL mutations and those with disruption of the genes encoding for succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD). A transcription profile of reduced oxidoreductase is detected in all three of these tumor types, together with an angiogenesis/hypoxia profile typical of VHL dysfunction. The oxidoreductase defect, not previously detected in VHL-null tumors, is explained by suppression of the SDHB protein, a component of mitochondrial complex II. The decrease in SDHB is also noted in tumors with SDHD mutations. Gain-of-function and loss-of-function analyses show that the link between hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1?. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1? activity in tumors.
2007-06-21 | E-GEOD-2841 | biostudies-arrayexpress
Project description:A Cartes d'Identité des Tumeurs (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net) | Affymetrix HG-U133 Plus 2.0 : 188 tumor samples |Pheochromocytomas and paragangliomas are neuroendocrine tumors occuring in the context of inherited cancer syndromes in approximately 30% of cases, linked to germline mutations in VHL, RET, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2 or TMEM127 genes. Although progress has been made with regard to tumorigenesis mechanisms in pheochromocytoma/paraganglioma thanks to genome-wide expression studies, the question of a putative molecular distinction between VHL- and SDHx- on one hand, and RET- and NF1-related tumors on the other hand, remained to be addressed as well as the characterization of genetic events in sporadic tumors. With this purpose, 202 pheochromocytomas/paragangliomas, including 75 hereditary tumors, were investigated by expression profiling, array CGH and somatic mutation screening. The systematic characterization of somatic genetic events associated with tumor suppressor gene germline mutations in tumor tissues reveals a majority of loss of heterozygosity (LOH) but also point mutations and copy neutral LOH. Gene-expression signature defined the hereditary tumors according to their genotype. Especially, a complete sub-separation between SDHx- and VHL-related tumors was observed. Moreover, guided by the transcriptome classification and the LOH profile, somatic mutations in VHL or RET genes were identified in 14% of sporadic pheochromocytomas/paragangliomas. A genetic cause was found in 45.5% (92/202) of the large series of pheochromocytomas/paragangliomas analyzed. Regarding mutated genes, specific molecular pathways involved in tumorigenesis mechanisms are showed. Altogether, these new findings suggest that somatic mutation analysis would give important clues for personalized molecular target therapies.
2011-07-07 | E-MTAB-733 | biostudies-arrayexpress
Project description:MicroRNAs are involved in the pathogenesis of several tumors, however, there have been no data on microRNA expression in pheochromocytomas to date. In this study we have performed microRNA expression profiling in sporadic benign, hereditary benign (multiplex endocrine neoplasia type 2-related and von Hippel-Lindau syndrome-related pheochromocytomas), and sporadic recurring adrenomedullary tumors. Due to the rarity of these neoplasms, the retrieval of sufficient quantities of fresh or immediately snap frozen tumor samples is difficult, therefore the applicability of formalin-fixed paraffin-embedded tissue samples for the analysis of microRNA expression in pheochromocytomas was examined.
2011-04-21 | GSE21767 | GEO
Project description:A Cartes d'Identité des Tumeurs (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net): Pheochromocytomas (PCC) and paragangliomas (PGL) are neural crest-derived tumors. We performed the integrated genomic analysis of a collection of PCC/PGL from the French COMETE network using SNP arrays, whole-exome sequencing, DNA methylation arrays, mRNA expression arrays and miRNA sequencing. We found that PCC/PGL are characterized by a low mutation rate, with few recurrent somatic mutations and focal copy number alterations (CNAs). In contrast, we detected recurrent broad CNAs strongly associated with known molecular groups, often leading to the biallelic inactivation of the known susceptibility genes of PCC/PGL. We also identified DNA methylation changes and miRNA expression clusters strongly associated with molecular groups. Of note, overexpression of the miRNA cluster 182/96/183 is specific of SDHB-mutated tumors and induces invasive traits, whereas silencing of the imprinted DLK1-MEG3 miRNA cluster due to a loss of heterozygosity of the 14q32.2 locus is a potential driver in a subset of sporadic tumors. This comprehensive analysis illustrates the functional interdependence between genomic and epigenomic dysregulations underlying PCC/PGL.
2015-02-02 | E-MTAB-2817 | biostudies-arrayexpress
Project description:A Carte d'Identitite des Tumeurs (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net): Pheochromocytomas (PCC) and paragangliomas (PGL) are neural crest-derived tumors. We performed the integrated genomic analysis of a collection of PCC/PGL from the French COMETE network using SNP arrays, whole-exome sequencing, DNA methylation arrays, mRNA expression arrays and miRNA sequencing. We found that PCC/PGL are characterized by a low mutation rate, with few recurrent somatic mutations and focal copy number alterations (CNAs). In contrast, we detected recurrent broad CNAs strongly associated with known molecular groups, often leading to the biallelic inactivation of the known susceptibility genes of PCC/PGL. We also identified DNA methylation changes and miRNA expression clusters strongly associated with molecular groups. Of note, overexpression of the miRNA cluster 182/96/183 is specific of SDHB-mutated tumors and induces invasive traits, whereas silencing of the imprinted DLK1-MEG3 miRNA cluster due to a loss of heterozygosity of the 14q32.2 locus is a potential driver in a subset of sporadic tumors. This comprehensive analysis illustrates the functional interdependence between genomic and epigenomic dysregulations underlying PCC/PGL.
2015-02-02 | E-MTAB-2833 | biostudies-arrayexpress
Project description:Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine, usually benign tumors. Currently, for these neoplasms the only reliable criterion of malignancy is the presence of metastases. The aim of the present study was to identify molecular markers that can distinguish malignant from benign PPGL. An mRNA expression array was performed on 40 benign and 11 malignant PPGL. Genes showing a significantly different expression between benign and malignant PPGL with a ratio ? 4 were selected. Differentially expressed genes were confirmed by qRT-PCR and subsequently tested in an independent validation series (4 benign and 4 malignant) by qRT-PCR. Finally, immunohistochemistry was performed for the validated genes on Tissue Micro Arrays, which included 100 PPGL (87 benign and 13 malignant). Ten genes, which were significantly differentially expressed between benign and malignant tumors (False Discovery Rates <0.05), were selected from the mRNA expression array data. Differential expression of Interleukin 13 Receptor Alpha 2 and Contactin 4 was confirmed (p<0.05) and validated by qRT-PCR. However, at the protein level, only Contactin 4 appeared to be significantly overexpressed in malignant tumors (58% in malignant versus 17% in benign; p<0.05). No difference in the immunohistochemical staining for Interleukin 13 Receptor Alpha 2 was observed between benign and malignant PPGL. Contactin 4 expression appears to be associated with malignancy in pheochromocytomas and paragangliomas, and may be predictive of malignant behavior.
2015-03-20 | GSE67066 | GEO
Project description:SNP profiles from 78 pheochromocytomas and paragangliomas were analyzed to detect copy number changes and LOH.
2012-09-11 | GSE38525 | GEO
Project description:SNP profiles from 30 pheochromocytomas and paragangliomas were analyzed to detect identical-by-descent haplotypes, highlighting a founder mutation of SDHD in two samples.
2012-03-23 | GSE32204 | GEO