Candidate Genes Associated With Malignant Pheochromocytomas by Genome-Wide Expression Profiling

Suh, Insoo; Shibru, Daniel; Eisenhofer, Graeme; Pacák, Karel; Duh, Quan‐Yang; Clark, Orlo H.; Kebebew, Electron

doi:10.1097/sla.0b013e3181b248bb

Cited by 24 publications

(21 citation statements)

References 33 publications

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“…Brouwers et al 38 examined 20 malignant tumors along with 70 sporadic and syndromic benign tumors: Gene Ontology Analysis of benign and malignant tumor comparison revealed the relevance of signal transduction changes. The significant gene sets established in two recent large-scale studies by Thouënnon et al 39 and Suh et al 40 are quite different, which indicates the need for further, large-scale gene expression profiling studies.…”

Section: Discussionmentioning

confidence: 95%

“…Transcriptomic studies representing targets of miRNA-based regulation are pivotal for the correct interpretation of miRNA findings. There have been six previous studies 11,[37][38][39][40][41] on gene expression profiling involving malignant pheochromocytomas to date. The studies of Dahia et al, 11 Björklund et al 37 and the most recent study of Waldmann et al 41 included only two, three and five malignant pheochromocytomas, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…40 The activation of 'Notch signaling' acts in a cell-specific manner, as it can be responsible for carcinogenesis by inhibiting differentiation, whereas in the nervous system it induces oligodendrocyte maturation and myelinization. 42 The valproic acid-induced activation of Notch1 pathway in PC12 rat pheochromocytoma cell line was associated with differentiation and growth inhibition.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas

et al. 2010

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MicroRNAs are involved in the pathogenesis of several tumors, however, there have been no data on microRNA expression in pheochromocytomas to date. The objective of our study was to perform microRNA expression profiling in sporadic and hereditary benign, and recurring adrenomedullary tumors. Furthermore, the applicability of formalin-fixed paraffin-embedded tissue samples for the analysis of microRNA expression in pheochromocytomas was examined. MicroRNA expression data of three matched frozen and formalin-fixed paraffin-embedded samples were correlated. A total of 21 formalin-fixed paraffin-embedded samples (sporadic benign, multiple endocrine neoplasia 2, von Hippel-Lindau disease, sporadic recurring) were subjected to microRNA expression profiling using microarrays. MicroRNAs with significant differences in expression were validated and sample sizes were extended including tumors from neurofibromatosis type 1 patients by real-time quantitative reverse-transcription PCR (n ¼ 33). MicroRNA target prediction was carried out by TargetScan and MicroCosm Targets. Pathway analysis of targets was performed by Ingenuity Pathway Analysis and DIANA mirPath. Furthermore, microRNA expression profiles of a malignant pheochromocytoma and a pair of primary and recurrent tumors were studied by TaqMan Human MicroRNA Cards. MicroRNA expression correlated well between frozen and formalin-fixed paraffinembedded samples (70-92%). Microarray analysis revealed 16 significantly differentially expressed microRNAs. Five of these were validated by real-time RT-PCR. miR-139-3p, miR-541 and miR-765 were significantly differentially expressed between sporadic benign and von Hippel-Lindau-related pheochromocytomas. Significantly higher expression of miR-885-5p and miR-1225-3p was found in multiple endocrine neoplasia type 2 and sporadic recurring pheochromocytomas, respectively. Pathway analysis revealed the possible involvement of Notch-and G-proteincoupled receptor signaling in tumor recurrence. MicroRNA expression profiles in the primary recurrent and recurring malignant comparisons have been similar. In conclusion, we have proved that formalin-fixed paraffinembedded samples can be used for the analysis of microRNA expression in pheochromocytomas. MicroRNA expression patterns differ between various sporadic, hereditary and recurring tumors and miR-1225-3p may be useful for identifying recurring pheochromocytomas.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas

et al. 2010

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“…Also, we emphasize that the expression of aHIF is highly variable, so it cannot be used as a marker of malignancy in individual patients. It is likely that individual risks of developing metastases can only be estimated by the use of a combination of clinical, biochemical, genetic, and molecular markers (Eisenhofer et al 2004, Suh et al 2009. In this context, protein expression of SNAIL, a zinc-finger transcription factor, has been identified as a useful marker of metastatic potential of PGL (Häyry et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the natural antisense hypoxia-inducible factor-1 transcript is associated with malignant pheochromocytoma/paraganglioma

Span

Rao²,

Ophuis³

et al. 2011

Endocrine Related Cancer

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Paragangliomas (PGLs) have widely different metastastic potentials. Two different types of PGLs can be defined by expression profiling. Cluster 1 PGLs exhibit VHL and/or succinate dehydrogenase (SDH) mutations and a pseudohypoxic phenotype. RET and neurofibromatosis type 1 (NF1) mutations occur in cluster 2 tumors characterized by deregulation of the RAS/RAF/MAP kinase signaling cascade. Sporadic PGLs can exhibit either profile. During sustained hypoxia, a natural antisense transcript of hypoxia-inducible factor 1 (aHIF) is expressed. The role of aHIF in the metastatic potential of PGL has not yet been investigated. The aim was to test the hypothesis that genotype-specific overexpression of aHIF is associated with an increased metastatic potential. Tumor samples were collected from 87 patients with PGL. Quantitative PCR was performed for aHIF, vascular endothelial growth factor (VEGF), aquaporin 3, cytochrome b561, p57Kip2, slit homolog 3, and SDHC. Expression was related to mutation status, benign versus malignant tumors, and metastasis-free survival. We found that both aHIF and VEGF were overexpressed in cluster 1 PGLs and in metastatic tumors. In contrast, slit homolog 3, p57Kip2, cytochrome b561, and SDHC showed overexpression in non-metastatic tumors, whereas no such difference was observed for aquaporin 3. Patients with higher expression levels of aHIF and VEGF had a significantly decreased metastasisfree survival. Higher expression levels of SDHC are correlated with an increased metastasis-free survival. In conclusion, we not only demonstrate a higher expression of VEGF in cluster 1 PGL, fitting a profile of pseudohypoxia and angiogenesis, but also of aHIF. Moreover, overexpression of aHIF and VEGF marks a higher metastatic potential in PGL.

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“…Malignant tumors can be diagnosed only after metastasis appearance (Kantorovich & Pacak 2010). Recent comparative microRNA and mRNA array studies made it possible to identify a set of genes that could discriminate benign from malignant tumors and to gain insights into the potential mechanisms underlying the occurrence of malignancy in pheochromocytomas (Thouënnon et al 2007, Suh et al 2009, Meyer-Rochow et al 2010, Waldmann et al 2010. In addition, we have demonstrated that EM66 levels increase significantly in the plasma of patients with pheochromocytomas (Guillemot et al 2006) and that low concentrations of this SgIIderived peptide in tumoral tissue are associated with malignancy (Yon et al 2003), indicating that EM66 may represent a valuable new diagnostic and prognostic marker of pheochromocytomas .…”

Section: Introductionmentioning

confidence: 99%

Differential expression and processing of secretogranin II in relation to the status of pheochromocytoma: implications for the production of the tumoral marker EM66

Guillemot¹,

Thouennon²,

Guérin³

et al. 2012

Journal of Molecular Endocrinology

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We have previously demonstrated that measurement of tissue concentrations of the secretogranin II (SgII or SCG2 as listed in the HUGO database)-derived peptide EM66 may help to discriminate between benign and malignant pheochromocytomas and that EM66 represents a sensitive plasma marker of pheochromocytomas. Here, we investigated the gene expression and protein production of SgII in 13 normal adrenal glands, and 35 benign and 16 malignant pheochromocytomas with the goal to examine the molecular mechanisms leading to the marked variations in the expression of EM66 in tumoral chromaffin tissue. EM66 peptide levels were 16-fold higher in benign than in malignant pheochromocytomas and had an area under the receiver-operating characteristic curve of 0 . 95 for the distinction of benign and malignant tumors. Q-PCR experiments indicated that the SgII gene was significantly underexpressed in malignant tumors compared with benign tumors. Western blot analysis using antisera directed against SgII and SgII-derived fragments revealed lower SgII protein and SgII-processing products in malignant tumors. Western blot also showed that low p-cAMP-responsive element-binding (CREB) concentrations seemed to be associated with the malignant status. In addition, the prohormone convertase PC1 and PC2 genes and proteins were overexpressed in benign pheochromocytomas compared with malignant pheochromocytomas. Low concentrations of EM66 found in malignant tumors are associated with reduced expression and production of SgII and SgII-derived peptides that could be ascribed to a decrease in SgII gene transcription, probably linked to p-CREB down-regulation, and to lower PC levels. These findings highlight the mechanisms leading to lower concentrations of EM66 in malignant pheochromocytoma and strengthen the notion that this peptide is a suitable marker of this neuroendocrine tumor.

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Candidate Genes Associated With Malignant Pheochromocytomas by Genome-Wide Expression Profiling

Abstract: Differentially expressed genes between benign and malignant pheochromocytomas distinguish between these tumors with high diagnostic accuracy. Our findings provide new insight into the genes and molecular pathways that may be involved in malignant pheochromocytomas.

Cited by 24 publications

References 33 publications

MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas

MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas

Overexpression of the natural antisense hypoxia-inducible factor-1 transcript is associated with malignant pheochromocytoma/paraganglioma

Differential expression and processing of secretogranin II in relation to the status of pheochromocytoma: implications for the production of the tumoral marker EM66

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