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Expression Profiling of pheochromocytomas of various genetic origins

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE2841 | GEO | 2005/08/12

SECONDARY ACCESSION(S): PRJNA92477

REPOSITORIES: GEO

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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.

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Expression Profiling of pheochromocytomas of various genetic origins

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