O1.07 * Intracranial Hemangiopericytomas Lack Typical Cytogenetic and Epigenetic Features of Meningiomas: A Comprehensive Molecular Genetic Study

Abstract

OBJECTIVE: Cranial hemangiopericytomas are rare tumors of mesenchymal origin with a high proclivity towards recurrence and extraneural metastasis. Considering the paucity of reports dealing with the tumor genetics of cranial hemangiopericytomas and the still ongoing debate about their histological standing, we examined a series of 9 cranial hemangiopericytomas for the most important meningioma specific cytogenetic and epi-genetic aberrations. Furthermore, for the first time, whole genomic imbalances were assessed by chromosomal CGH analysis. MATERIAL AND METHODS: In a total of nine histopathologically confirmed CNS-hemangio-pericytomas, the promoter methylation status of p15(CDKN2B), p16INK4A, TIMP3, MGMT and NDRG2 genes were evaluated via MS-PCR and direct bisulfite sequencing, respectively. Furthermore, typical numerical chromosomal aberrations reported in meningiomas were investigated using two-color FISH on touchpreparations with locus specific probe pairs detecting 1p36/22q11, 14q24/ 18q21, and 9p21/10q23 (MetaSystems, Altlußheim, Germany). For CGH analysis, standard procedures were used. RESULTS: All studied cases presented with an unmethylated status of the p15, MGMT and TIMP3 promoters. One specimen was encountered with positive methylation signal for p16 in MS-PCR analysis. Direct bisulfite sequencing for NDRG2 revealed only in 1/6 cases a moderately elevated average methylation degree. In FISH analyses, disomy for all targeted chromosomal regions was found in 5/9 studied hemangiopericytoma specimens; in two tumors a slight clone with hemizygous loss of 10q23 was detected. In one other specimen, virtually all nuclei harbored a hemizygous deletion of 9p21. One further CNS-hemangiopericytoma was characterized by a tetraploid mainline with slight sidelines that contained trisomies of 9p21 and 10q23. CGH analysis revealed heterogeneous copy number changes for each of the nine hemangiopericytomas (8.2 alterations on average), involving all chromosomes besides chromosomes 14, 15, and 21. Most frequently, chromosomes 4 and 18 were affected by DNA changes. On subchromosomal level, most recurrent aberrations involved the exclusive gains on 7q11.2, 16p13.2 p13.3, and 18p11.3 as well as the exclusive segmental loss of 20q13.2 q13.3. CONCLUSIONs: Most CNS-hemangiopericytomas obviously lack meningioma specific epigenetic and molecular cytogenetic lesions, further providing evidence that they represent a distinct tumor entity with genetic different features. The present findings prompt one to speculate about the possible role of inactivation of p16INK4a and deletions on 10q in the underlying tumorigenesis of a distinct subgroup of CNS-hemangiopericytomas. By use of CGH analysis, novel regions of gains and losses were identified which will help to further elucidate potentially causal genetic events for genesis of cranial hemangiopericytomas.