Retinoblastoma - Cyclin-dependent kinase pathway deregulation in vestibular schwannomas

Objectives. The purpose of the study was to identify genes of the retinoblastoma protein (pRb)-cyclin-dependent kinase (CDK) pathway that are deregulated in vestibular schwannomas when compared with normal vestibular nerve tissues. Study Design: Expression profiles in eight vestibular schwannomas (four sporadic tumors, one neurofibromatosis type 2 tumor, and three cystic tumors) and a paired normal vestibular nerve from one of the eight patients were chosen. Genes examined included the retinoblastoma susceptibility gene (Rb-1); cyclins D1, D2, A, and E; the CDK inhibitors p18, p19, and p27; CDK2 and CDK6; transcription factors E2F4, E2F-5, and DP-1; and the neurofibromatosis type 2 gene. Methods. Total RNA samples were extracted from normal vestibular nerve and vestibular schwannoma tissues and used to generate radiolabeled complementary DNA (cDNA) samples. Labeled cDNA probes were then hybridized to cDNA microarray filters. The hybridization signal was captured and quantified. Differential gene expression profiles between the normal vestibular nerve and vestibular schwannoma were compared. Real-time polymerase chain reaction and immunohistochemistry were used to further confirm the cDNA microarray data. Results. Among genes in the pRb-CDK pathway, CDK2 was substantially underexpressed in seven of the eight vestibular schwannoma tumors examined. Quantitative RNA expression analysis using real-time polymerase chain reaction also showed consistent downregulation of CDK2 in the tumors. Anti-CDK2 antibody stained predominantly in the vestibular nerve and ganglion cells but only weakly in the vestibular schwannoma tissues. Conclusions. The pRb-CDK pathway was altered in all vestibular schwannoma tumors examined, with CDK2 significantly downregulated in seven of the eight tumors. Further investigation into the regulatory mechanisms governing CDK2 expression may lead to a better understanding of vestibular schwannoma tumorigenesis.