Global Gene Expression Profiling and Tissue Microarray Reveal Novel Candidate Genes and Down-Regulation of the Tumor Suppressor Gene CAV1 in Sporadic Vestibular Schwannomas

Abstract

The vestibular nerve is the predilection site for schwannomas. Few transcriptomic studies have been performed on solely sporadic vestibular schwannomas (VSs). To detect genes with altered expression levels in sporadic VSs. We studied 25 VSs and 3 tibial nerves (controls) with the ABI 1700 microarray platform. Significance analysis of microarrays was performed to explore differential gene expression. Selected genes were validated with quantitative reverse transcriptase polymerase chain reaction. A tissue microarray was constructed for immunohistochemistry. Neurofibromatosis type II cDNA was sequenced for mutations. The VSs formed 2 clusters based on the total expression of 23,055 genes. Tumor size, previous Gamma Knife surgery, neurofibromatosis type II mutations, and cystic tumors were distributed equally in both. Significance analysis of microarrays detected 1650 differentially expressed genes. On the top 500 list, several cancer-related genes with an unrecognized role in VSs were down-regulated: CAV1, TGFB3, VCAM1, GLI1, GLI2, PRKAR2B, EPHA4, and FZD1. Immunohistochemistry showed no CAV1 expression in the VSs. The ERK pathway was the central core in the network linking the differentially expressed genes. The previously reported VS candidate genes SPARC, PLAT, and FGF1 were up-regulated. Nineteen of 25 VSs had NF2 mutations. Using microarray technology, we identified novel genes and pathways with a putative role in VSs, confirmed previous candidate genes, and found cancer-related genes with no reported role in VSs. Among these, down-regulation of CAV1 at both the mRNA and protein levels is of particular interest because this tumor suppressor normally is expressed in Schwann cells.