Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of pheochromocytomas and paragangliomas (188 tumor samples)

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Laure Vescovo

PROVIDER: E-MTAB-733 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Integrative analysis of neuroblastoma and pheochromocytoma genomics data.

Szabó Peter M PM Pintér Miklós M Szabó Diana Rita DR Zsippai Adrienn A Patócs Attila A Falus András A Rácz Károly K Igaz Peter P

BMC medical genomics 20121029

<h4>Background</h4>Pheochromocytoma and neuroblastoma are the most common neural crest-derived tumors in adults and children, respectively. We have performed a large-scale in silico analysis of altogether 1784 neuroblastoma and 531 pheochromocytoma samples to establish similarities and differences using analysis of mRNA and microRNA expression, chromosome aberrations and a novel bioinformatics analysis based on cooperative game theory.<h4>Methods</h4>Datasets obtained from Gene Expression Omnibu ...[more]

PMID: 23106811

Publication: 1/2

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Project description:Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine neoplasias of neural crest origin. They can be part of several syndromes, and their mRNA profile is dependent on genetic background, but questions related to clinical behavior or even main location remain unanswered. MicroRNAs are key modulators of target genes through translational repression, mRNA degradation, or both, and therefore they could resolve some of these issues. To determine the role microRNAs play in tumorigenesis and progression of PCC/PGL, as well as to identify microRNA biomarkers specifically related to different PCC/PGL genetic classes known so far, we characterized microRNA profiles in a large series of frozen tumors with germline mutations in SDHD, SDHB, VHL, RET, NF1, and TMEM127 genes through microarray analysis. We identified microRNA signatures specific to, as well as common among, the genetic classes of PCC/PGLs, and the best candidate microRNAs (miR-122, miR-126*, miR-129*, miR-133b, miR-137, miR-183, miR-210, miR-382, miR-488, miR-885-5p, and miR-96) were validated in an independent series of formalin-fixed paraffin-embedded PCC/PGL samples by qRT-PCR. MicroRNA-137, -96/183, and -143/145 expression in PCC/PGLs correlated inversely with the differentiation status of tumor cells. MicroRNA-210, -382, and -380 could modulate pseudohypoxic cellular response in VHL-deficient PCC/PGL. MicroRNA-193b, -365, and -424 were commonly downregulated among all genetic classes, suggesting their involvement in cell cycle control and differentiation. Herein, we demonstrate that PCC/PGLs have different microRNA profiles according to the underlying primary mutation, suggesting they could be used as specific biomarkers and add information on the etiology of these tumors. For this study, we employed the Agilent-019118 Human miRNA Microarray 2.0 G4470B (with Labeling kit: Agilent miRNA labeling reagent and Hybridization Kit, Cat # 5190-0408) to perform microRNA expression profiling on a large series of 54 fresh-frozen tissue samples, including a total of 48 genetically characterized pheochromocytomas (n=37) and paragangliomas (n=11) (8 SDHB-related tumors, 4 SDHD-related tumors, 14 Ret-related tumors, 12 VHL-related tumors, 4 NF1-related tumors, 3 TMEM127-related tumors, and 3 familial pheochromocytoma (FPCC) samples), and 6 normal adrenal medulla. Normalization of array data was performed applying the robust multiarray average (RMA) method using the AgiMicroRna package in Bioconductor. RMA normalization, by default, merges replicates of each probe and produces an Eset with a single value for each microRNA.

Dataset Information

Transcription profiling of pheochromocytomas and paragangliomas (188 tumor samples)

Publications

Integrative analysis of neuroblastoma and pheochromocytoma genomics data.

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