Cyclin D1 Expression and Histopathologic Features in Vestibular Schwannomas

International Journal of Oncology

San-Román-Montero

et al. 2013

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Vestibular schwannomas are benign neoplasms that arise from the vestibular nerve. The hallmark of these tumors is the biallelic inactivation of neurofibromin 2 (NF2). Transcriptomic alterations, such as the neuregulin 1 (NRG1)/ErbB2 pathway, have been described in schwannomas. In this study, we performed a whole transcriptome analysis in 31 vestibular schwannomas and 9 control nerves in the Affymetrix Gene 1.0 ST platform, validated by quantitative real-time PCR (qRT-PCR) using TaqMan Low Density arrays. We performed a mutational analysis of NF2 by PCR/denaturing high-performance liquid chromatography (dHPLC) and multiplex ligation-dependent probe amplification (MLPA), as well as a microsatellite marker analysis of the loss of heterozygosity (LOH) of chromosome 22q. The microarray analysis demonstrated that 1,516 genes were deregulated and 48 of the genes were validated by qRT-PCR. At least 2 genetic hits (allelic loss and/or gene mutation) in NF2 were found in 16 tumors, seven cases showed 1 hit and 8 tumors showed no NF2 alteration. MET and associated genes, such as integrin, alpha 4 (ITGA4)/B6, PLEXNB3/SEMA5 and caveolin-1 (CAV1) showed a clear deregulation in vestibular schwannomas. In addition, androgen receptor (AR) downregulation may denote a hormonal effect or cause in this tumor. Furthermore, the osteopontin gene (SPP1), which is involved in merlin protein degradation, was upregulated, which suggests that this mechanism may also exert a pivotal role in schwannoma merlin depletion. Finally, no major differences were observed among tumors of different size, histological type or NF2 status, which suggests that, at the mRNA level, all schwannomas, regardless of their molecular and clinical characteristics, may share common features that can be used in their treatment.

Section: Introductionsupporting

confidence: 92%

Microarray analysis of gene expression in vestibular schwannomas reveals SPP1/MET signaling pathway and androgen receptor deregulation

Torres‐Martín

International Journal of Oncology

San-Román-Montero

et al. 2013

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“…Patients with positive cyclin D1 expression had better facial function outcome. In a previous study, we found an association between cyclin D1 expression and cellular degenerative changes (8). As these changes may reflect long-term, that is, less aggressive lesions, this could explain why overexpression of a proto-oncogen is associated with a favorable facial outcome.…”

Section: Discussionmentioning

confidence: 78%

“…Immunohistochemical cyclin D1 expression has been recently described in 52% of 22 patients with VS. Cyclin D1 expression was more frequent in tumors with nuclear degenerative changes, as well as in patients with longer duration of deafness and higher (2,000 Hz) hearing thresholds (8).…”

mentioning

confidence: 99%

Cyclin D1 Expression and Facial Function Outcome After Vestibular Schwannoma Surgery

Otology &Amp; Neurotology

Rı́o²,

Torres‐Martín³

et al. 2011

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“…Cyclin D1 is a cell-cycle regulatory protein for the mammalian G1-S phase transition and is implicated in cell proliferation and differentiation. Lassaletta et al [85] found, using immunohistochemistry, cyclin D1 expression in 52% of their cases. This deregulated gene was more frequently present in tumors with nuclear degenerative changes (Figure 1).…”

Section: Deregulated Genes In Vestibular Schwannomamentioning

confidence: 99%

The Molecular Biology of Vestibular Schwannomas and Its Association with Hearing Loss: A Review

Celis‐Aguilar

Genetics Research International

Torres‐Martín

et al. 2012

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Hearing loss is the most common symptom in patients with vestibular schwannoma (VS). In the past, compressive mechanisms caused by the tumoral mass and its growth have been regarded as the most likely causes of the hearing loss associated with VS. Interestingly, new evidence proposes molecular mechanisms as an explanation for such hearing loss. Among the molecular mechanisms proposed are methylation of TP73, negative expression of cyclin D1, expression of B7-H1, increased expression of the platelet-derived growth factor A, underexpression of PEX5L, RAD54B, and PSMAL, and overexpression of CEA. Many molecular mechanisms are involved in vestibular schwannoma development; we review some of these mechanisms with special emphasis on hearing loss associated with vestibular schwannoma.