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Valverde de la Virgen, Spain

Torres-Martin M.,University Institute of La Paz | Lassaletta L.,University Institute of La Paz | San-Roman-Montero J.,Rey Juan Carlos University | De Campos J.M.,Jimenez Diaz Foundation | And 7 more authors.
International Journal of Oncology | Year: 2013

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. Source


Torres-Martin M.,Hospital Universitario La Paz | Martinez-Glez V.,Hospital Universitario La Paz | Pena-Granero C.,Hospital Universitario La Paz | Lassaletta L.,Hospital Universitario La Paz | And 7 more authors.
Clinical and Translational Oncology | Year: 2013

Purpose Gene expression array analysis is providing key data on the potential candidate genes and biological pathways involved in schwannoma origin and development. In this way we performed expression array studies on tumorrelated genes in schwannomas. Methods The GE Array Q Series HS-006 (SuperArray, Bethesda, MD, USA) was used to determine the expression levels of 96 genes corresponding to 6 primary biological regulatory pathways in a series of 23 schwannomas. Results We identified 15 genes down-regulated, primarily corresponding to signal transduction functions, and 26 genes up-regulated, most frequently involving cell adhesion functions. Conclusions In addition to the NF2 inactivation (considered as an early step), variations of other biological regulatory pathways might play a key role in schwannoma. © Federación de Sociedades Españolas de Oncología (FESEO) 2012. Source


Ruano Y.,Molecular Pathology Research Unit
Methods in molecular biology (Clifton, N.J.) | Year: 2010

Alterations in the genome that lead to changes in DNA sequence copy number are a characteristic of Glioblastomas (GBs). Microarray-based comparative genomic hybridization (array-CGH) is a high-throughput technology that allows the hybridization of genomic DNA onto conventional cDNA microarrays, normally used in expression profiling, to analyze genomic copy number imbalances. In this way, thousands of genes can be reviewed in a high resolution analysis to define amplicons and to identify? candidate genes showing recurrent genomic copy number changes in GB tumors. Source


Torres-Martin M.,Hospital Universitario La Paz | Lassaletta L.,Hospital Universitario La Paz | de Campos J.M.,Fundacion Jimenez Diaz | Isla A.,Hospital Universitario La Paz | And 7 more authors.
PLoS ONE | Year: 2013

Background:Vestibular schwannomas are benign tumors that arise from Schwann cells in the VIII cranial pair and usually present NF2 gene mutations and/or loss of heterozygosity on chromosome 22q. Deregulation has also been found in several genes, such as ERBB2 and NRG1. MicroRNAs are non-coding RNAs approximately 21 to 23 nucleotides in length that regulate mRNAs, usually by degradation at the post-transcriptional level.Methods:We used microarray technology to test the deregulation of miRNAs and other non-coding RNAs present in GeneChip miRNA 1.0 (Affymetrix) over 16 vestibular schwannomas and 3 control-nerves, validating 10 of them by qRT-PCR.Findings:Our results showed the deregulation of 174 miRNAs, including miR-10b, miR-206, miR-183 and miR-204, and the upregulation of miR-431, miR-221, miR-21 and miR-720, among others. The results also showed an aberrant expression of other non-coding RNAs. We also found a general upregulation of the miRNA cluster located at chromosome 14q32.Conclusion:Our results suggest that several miRNAs are involved in tumor formation and/or maintenance and that global upregulation of the 14q32 chromosomal site contains miRNAs that may represent a therapeutic target for this neoplasm. © 2013 Torres-Martin et al. Source


Perez-Magan E.,Molecular Pathology Research Unit | Campos-Martin Y.,Molecular Pathology Research Unit | Mur P.,Molecular Pathology Research Unit | Fiano C.,Xeral Cies Hospital Complex | And 6 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2012

Meningiomas are the most common primary brain tumors; they arise from the coverings of the brain. Although meningiomas are generally benign, some are more clinically aggressive, as reflected by their histopathological features or by their unexpected recurrence. We hypothesized that recurrent histologically benign meningiomas might have genetic features in common with those showing a more aggressive histology. By comparing gene expression profiles associated with meningioma progression and recurrence in 128 tumor samples (i.e. 83 benign World Health Organization [WHO] Grade I, 37atypical WHO Grade II, and 8 anaplastic WHO Grade III) from121patients, we identified a 49-gene signature of meningioma aggressivity. This signature classified the tumors into 2 groups showing different clinical and pathological behaviors. The signature was composed of genes involved in the cell cycle (TMEM30B, CKS2, and UCHL1) and other pathways previously described as being altered in meningiomas, that is, WNT (SFRP1 and SFRP4) and transforming growth factor-β pathways (LTBP2 and LMO4). Overall, gene downregulation was observed in advanced and recurrentsamples versus benign and original ones. We propose that this gene repression may be caused by gene promoter hypermethylation, as in the case of UCHL1 and SFRP1, suggesting that this epigenetic event, together with loss of specific chromosomal regions, may play an important role in meningioma progression and recurrence. Copyright © 2012 by the American Association of Neuropathologists, Inc. Source

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