Selective loss of chromosome 11 in pheochromocytomas associated with the VHL syndrome

Lui, Weng‐Onn; Chen, Jindong; Gläsker, Sven; Bender, Bernhard U.; Madura, Casey; Khoo, Sok Kean; Kort, Eric J.; Larsson, Catharina; Neumann, H. P. H.; Teh, Bin Tean

doi:10.1038/sj.onc.1205149

Cited by 46 publications

(53 citation statements)

References 19 publications

(17 reference statements)

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“…Loss of 3p or that of whole chromosome 3 could be detected in 94% of von Hippel-Lindau disease pheochromocytomas. 35 Among the hypoxiaresponsive/angiogenesis genes previously described to be significantly underexpressed in multiple endocrine neoplasia type 2 relative to von Hippel-Lindau disease pheochromocytomas, 11 laminin subunits (LAMB4, LAMA5, LAMC2), collagene type 4 (COL4A5) and proline 4-hydroxilase a-1 precursor (P4HA1) could be identified to be targets potentially downregulated by miR-885-5p by our in silico target prediction approach.…”

Section: Discussionmentioning

confidence: 87%

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: 87%

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

et al. 2010

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“…This pattern of loss has been previously mentioned in PCC from VHL patients, but has so far not been related to a subgroup of sporadic PCC (Lui et al 2002, Hering et al 2006. In order to exclude that this subgroup represented occult VHL disease, we performed mutation analysis of the entire VHL coding region, in which we could not detect germline mutations.…”

Section: Discussionmentioning

confidence: 99%

“…VHL-related PCC, however, show distinct genetic aberrations consisting of loss of chromosomes 3 and 11 (Lui et al 2002, Hering et al 2006.…”

Section: Introductionmentioning

confidence: 99%

Array-comparative genomic hybridization in sporadic benign pheochromocytomas

Nederveen¹,

Korpershoek²,

deLeeuw³

et al. 2009

Endocrine-Related Cancer

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Pheochromocytomas (PCC) are catecholamine-producing tumors arising from the adrenal medulla that occur either sporadically or in the context of hereditary cancer syndromes, such as multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease (VHL), neurofibromatosis type 1, and the PCC-paraganglioma syndrome. Conventional comparative genomic hybridization studies have shown loss of 1p and 3q in the majority of sporadic and MEN2-related PCC, and 3p and 11p loss in VHL-related PCC. The development of a submegabase tiling resolution array enabled us to perform a genome-wide high-resolution analysis of 36 sporadic benign PCC. The results show that there are two distinct patterns of abnormalities in these sporadic PCC, one consisting of loss of 1p with or without concomitant 3q loss in 20/36 cases (56%), the other characterized by loss of 3p with or without concomitant 11p loss in 11/36 (31%). In addition, we found loss of chromosome 22q at high frequency (35%), as well as the novel finding of high frequency chromosome 21q loss (21%). We conclude that there appear to be two subgroups of benign sporadic PCC, one of which has a pattern of chromosomal abnormalities that is comparable with PCC from patients with MEN2 and the other that is comparable with the PCC that arise in patients with VHL disease. In addition, genes on 21q and 22q might play a more important role in PCC pathogenesis than had been assumed thus far.

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“…Loss involving the long arm of chromosome 11 (11q) has been reported in almost 70% of VHL-associated PCCs [19] but no specific additional PCC triggering gene has yet been identified.…”

Section: Introductionmentioning

confidence: 99%

Role of SDHAF2 and SDHD in von Hippel–Lindau Associated Pheochromocytomas

et al. 2013

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Pheochromocytomas (PCCs) develop from the adrenal medulla and are often part of a hereditary syndrome such as von Hippel Lindau (VHL) syndrome. In VHL, only about 30% of patients with a VHL missense mutation develop PCCs. Thus, additional genetic events leading to formation of such tumors in patients with VHL syndrome are sought for. SDHAF2 (previously termed SDH5) and SDHD are both located on chromosome 11q and required for the function of mitochondrial complex II. While SDHAF2 has been shown to be mutated in patients with paragangliomas (PGLs), SDHD mutations have been found in both patients with PCCs and PGLs. Since loss of 11q is a common event in VHLassociated PCCs, we aimed to investigate whether SDHAF2 and SDHD are targets. In this study, 41 VHL-associated PCCs were screened for mutations and loss of heterozygosity (LOH) in SDHAF2 or SDHD. Promoter methylation as well as mRNA expression of SDHAF2 and SDHD was studied. In addition, immunohistochemistry (IHC) of SDHB, known to be a universal marker for loss of any part the SDH complex, was conducted. LOH was found in more than 50% of the VHL-associated PCCs, and was correlated to a significant decrease (p<0.05) in both SDHAF2 and SDHD mRNA expression, which may be suggestive of a pathogenic role. However, while SDHB protein expression as determined by IHC in a small cohort of tumors was lower in PCCs than in the surrounding adrenal cortex, there was no obvious correlation with LOH or the level of SDHAF2/SDHD mRNA expression.In addition, the lack of mutations and promoter methylation in the investigated samples indicate that other events on chromosome 11 might be involved in the development of PCCs in association with VHL syndrome.3

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Selective loss of chromosome 11 in pheochromocytomas associated with the VHL syndrome

Cited by 46 publications

References 19 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

Array-comparative genomic hybridization in sporadic benign pheochromocytomas

Role of SDHAF2 and SDHD in von Hippel–Lindau Associated Pheochromocytomas

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