Lack of genetic and epigenetic changes in meningiomas without NF2 loss.
Approximately 60% of sporadic meningiomas are caused by inactivation of the NF2 tumour suppressor gene. The causative gene for the remaining meningiomas is unknown. Previous studies have shown that these tumours have no recurrent karyotypic abnormalities. They differ from their NF2-related counterparts in that they are more often of the meningothelial subtype and are located preferentially in the anterior skull base. To gain more insight into the aetiology of these tumours, we studied genetic and epigenetic alterations in 25 meningiomas without NF2 involvement. We first established a genome-wide allelotype using 3 microsatellite markers per chromosome arm. Loss of heterozygosity (LOH) was detected at a low frequency and no indication for the location of putative tumour suppressor genes could be established. We next screened the subtelomeric regions by using 2-3 polymorphic markers close to each telomere. Again no evidence for LOH of a particular chromosome arm was obtained, and no LOH was found in the genomic regions containing the NF2-related ERM family members ezrin and radixin, DAL-1, protein 4.1R, and TSLC1. Mutations in the X-chromosome based family member, moesin, were analysed by SSCP and were not detected. Microsatellite instability was studied using 6 commonly used markers but none of these was altered in any meningioma. Methylation was detected in 5 of 16 genes (NF2, p14(ARF), CDH1, BRCA1, RB1) previously shown to be silenced in a variety of tumour types. However, methylation percentages for these genes were generally higher in a group of NF2-related meningiomas, with the exception of the BRCA1 gene. The NF2 gene was methylated in only 1 of 21 tumours. In conclusion, meningiomas with an intact NF2 gene have a normal karyotype and no obvious genetic or epigenetic aberrations, suggesting that the gene(s) involved in the pathogenesis of these tumours are altered by smaller events than can be detected with the techniques used in our study.
van Tilborg
Angela A G
AA
Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands.
Morolli
Bruno
B
Giphart-Gassler
Micheline
M
de Vries
Annie
A
van Geenen
Daniëlle A N
DA
Lurkin
Irene
I
Kros
Johan M
JM
Zwarthoff
Ellen C
EC
D000328:Adult; D000368:Aged; D000483:Alleles; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D019398:Genes, BRCA1; D005819:Genetic Markers; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008579:Meningioma / Q000235:genetics*; D018895:Microsatellite Repeats; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D025581:Neurofibromin 2 / Q000235:genetics; D018807:Polymorphism, Single-Stranded Conformational; D019292:Skull Base Neoplasms / Q000235:genetics*
D005819:Genetic Markers; D009363:Neoplasm Proteins; D025581:Neurofibromin 2