Anatomic Pathology / EXPRESSION OF MOS IN EPENDYMAL GLIOMAS Expression of mos in Ependymal Gliomas

The c-mos gene and its protein product mos, components of the mitogen-activated protein kinase transduction pathway, are known to be involved in the control of meiosis and mitosis. Apart from our previous studies on lung carcinomas and astrocytic gliomas, little has been published about its role in human neoplasia. The aim of this study was to investigate the expression of mos in ependymal neoplasms and to correlate it with tumor grade, proliferative fraction, and clinical behavior. We studied mos expression in biopsy specimens from 34 patients with ependymomas. Intracytoplasmic immunopositivity for mos was found in 16 (47%) and was associated significantly with tumor grade: 5 (24%) of 21 grade II ependymomas; 11 (85%) of 13 grade III anaplastic ependymomas (P < .01). Tumors with an MIB-1 labeling index of more than 4% were significantly more likely than those with a lower proliferative fraction to be immunopositive for mos (P = .012). Expression of mos showed a significant negative association with recurrence-free interval (P = .05) but not with overall survival. Our results suggest that overexpression of mos identifies a biologically aggressive subgroup of ependymal tumors and may be involved in their neoplastic progression. c-mos, the proto-oncogene located in humans on chromosome 8q11-12, encodes mos, a 39-kd protein that is a component of the mitogen-activated protein kinase (MAPK) transduction pathway.1 Much of the research to date on mos has concerned its role in meiosis. Its functions as a regulator of meiotic maturation, essential for meiosis I and meiosis II, have been the subject of several comprehensive reviews.1-3 mos or its coding messenger RNA have been demonstrated at low levels in most somatic tissues.4-6 High levels of mos were reported to cause somatic cell death,7 which probably results from p53-mediated growth arrest and apoptosis.8 In addition, increased expression of c-mos has been linked to neoplastic transformation of some somatic cells.9 Our understanding of this proneoplastic action is still incomplete. It has been suggested that overexpression of c-mos may cause cells to acquire a meiosis-like phenotype, with compromise of the mitotic checkpoints that normally ensure integrity of genetic material and symmetry of cell division during mitosis.8,10,11 An alternative proposal is that altered MAPK activity resulting from overexpression of c-mos interferes with normal cyclin D1-Cdk4-pRb-E2F signaling.1,12,13 Loss of p53 cell checkpoint activity is thought to be one of the permissive events in this process.8 Athanasiou et al14 and Gorgoulis et al15 showed increased transcription of c-mos and elevated levels of immunostainable mos in a high proportion of human lung carcinomas. More recently, Perunovic et al16 found a significant correlation between the expression of mos and the grade of astrocytic glioma. The present study concerns the expression of mos in ependymomas. From a molecular genetic and a histologic perspective, ependymomas are distinct from astrocytic tumors.17 Consistent Am J Clin Pathol 2003;120:699-705 699 699 DOI: 10.1309/DL2TLDJG7JB1BQ72 699 © American Society for Clinical Pathology Athanasiou et al / EXPRESSION OF MOS IN EPENDYMAL GLIOMAS alterations of the major cellular regulatory pathways that have been reported in astrocytic tumors, such as mutations of EGFR, PTEN, and p16CDKN2a, have not been observed in most ependymomas.18-23 Furthermore, histologic features are less reliable predictors of the biologic behavior of ependymal than of astrocytic gliomas.17 Our aim was to study the expression of mos in ependymal tumors of different histologic grades and to correlate expression with the recurrence-free interval and total survival. In addition, because the proliferative fraction of the tumor, as determined by immunohistochemical analysis with MIB-1 antibody to Ki-67, has been shown to correlate inversely with survival in patients with ependymoma,24,25 we were interested to find out whether the expression of mos correlated with the MIB-1 labeling index (MIB-1 LI) in this type of tumor. Materials and Methods