Molecular genetic alterations on chromosomes 11 and 22 in ependymomas

Ependymomas arise from the ependymal cells at different locations throughou t the brain and spinal cord. These tumors have a broad age distribution wit h a range from less than I year to more than 80 years. In some intramedulla ry spinal ependymomas, mutations in the neurofibromatosis 2 (NF2) gene and loss of heterozygosity (LOH) on chromosome arm 22q have been described. Cyt ogenetic studies have also identified alterations involving chromosome arm I Iq, including rearrangements at 11q13, in ependymomas. We analyzed 21 int ramedullary spinal, 14 ventricular, I I filum terminate and 6 intracerebral ependymomas for mutations in the MENI gene, which is located at 11q13, and mutations in the NF2 gene, which is located at 22q 12, as well as for LOH on 11q and 22q, NF2 mutations were found in 6 tumors, all of which were int ramedullary spinal and all of which displayed LOH 22q. Allelic loss on 22q was found in 20 cases and was significantly more frequent in intramedullary spinal ependymomas than in tumors in other locations. LOH 11q was found in 7 patients and exhibited a highly significant inverse association with LOH 22q (p<0.001), A hemizygous MENI mutation was identified in 3 tumors, all of which were recurrences from the same patient. Interestingly, the initial tumor corresponded to WHO grade II and displayed LOH I Iq but not yet a ME NI mutation. In 2 subsequent recurrences, the tumor had progressed to anapl astic ependymoma (WHO grade III) and exhibited a nonsense mutation in exon 10 of MENI (W471X) in conjunction with LOH I Iq, This suggests that loss of wildtype MENI may be involved in the malignant progression of a subset of ependymomas. To conclude, our findings provide evidence for different genet ic pathways involved in ependymoma formation and progression, which may all ow to define genetically and clinically distinct tumor entities. (C) 2001 W iley-Liss, Inc.