Dataset Information

Expression data from pheochromocytoma (PHEO) and paraganglioma (PGL) tumor samples

ABSTRACT: Genotype specific differences in expression profiles have been evaluated using human HuGene1.0-ST Gene Chips. In this dataset we include expression data obtained from 8 normal adrenal medulla and 45 PHEOs/PGLs patient samples. Viable appearing tissue from the center of the lesions was collected and snap frozen for RNA extraction. Each of the 45 PHEO/PGL samples was examined by pathologist upon resection. Patients PKh_27 and PKh_28 with SDHB mutation were from the same patient with samples taken from two different locations at different times. Diagnosis of PHEO/PGL has been confired in all cases histopathologically. The tissues were grouped according to genetic/syndromic background and tumor location into SDHB (n = 18), SDHD-A/T (n = 6), SDHD-HN (n= 8), and VHL (n = 13).

ORGANISM(S): Homo sapiens

PROVIDER: GSE39716 | GEO | 2013/11/12

SECONDARY ACCESSION(S): PRJNA171564

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.

Project description:BackgroundPheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease. We hypothesized that a down-regulation in the active succinate dehydrogenase B subunit should result in notable changes in cellular metabolic profile and could present a vulnerability point for successful pharmacological targeting.MethodsMetabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 115 human fresh frozen samples was conducted. In vitro studies using N1,N11-diethylnorspermine (DENSPM) and N1,N12- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in human cell line derived mouse xenografts.ResultsComponents of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tissues compared to their non-mutated counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts.ConclusionsThis study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine pathway inhibitors significantly inhibited hPheo1 cell growth and led to growth suppression in xenograft mice treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL. PRéCIS: Cell line metabolomics on hPheo1 cells and PCC/PGL tumor tissue indicate that the polyamine pathway is activated. Polyamine inhibitors in vitro and in vivo demonstrate that polyamine inhibitors are promising for malignant PCC/PGL treatment. However, further research is warranted.

Dataset Information

Expression data from pheochromocytoma (PHEO) and paraganglioma (PGL) tumor samples

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