Microarray analysis of gene expression in vestibular schwannomas reveals             SPP1/MET signaling pathway and androgen receptor deregulation.
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.
Research Unit, La Paz University Hospital, Hospital La Paz Institute for Health Research (IdiPAZ), 28046 Madrid, Spain. migtorres.martin@gmail.com
Miguel
M
Torres-Martin
Luis
L
Lassaletta
Jesus
J
San-Roman-Montero
Jose M
JM
De Campos
Alberto
A
Isla
Javier
J
Gavilan
Barbara
B
Melendez
Giovanny R
GR
Pinto
Rommel R
RR
Burbano
Javier S
JS
Castresana
Juan A
JA
Rey
D017398:Alternative Splicing; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D051242:Caveolin 1 / Q000096:biosynthesis / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D015536:Down-Regulation; D066246:ErbB Receptors / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D039441:Integrin alpha4 / Q000235:genetics; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism*; D009464:Neuroma, Acoustic / Q000235:genetics* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D012583:Schwann Cells / Q000473:pathology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D051242:Caveolin 1; D066246:ErbB Receptors; D006360:Heat-Shock Proteins; D039441:Integrin alpha4; D020890:Neuregulin-1; D025581:Neurofibromin 2; D053495:Osteopontin; D019859:Proto-Oncogene Proteins c-met; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011944:Receptors, Androgen; D016212:Transforming Growth Factor beta; D054462:p21-Activated Kinases; C094131:NRG1 protein, human; C506895:SPP1 protein, human; C101296:prostate apoptosis response-4 protein; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C491743:MET protein, human; C515907:PAK2 protein, human; C515911:PAK3 protein, human