In approximately 60% of sporadic meningiomas, the tumour suppressor gene NF2, located on chromosome 22q, is inactivated. Mutations in the NF2 gene have been specifically reported in transitional and fibrous, but not meningothelial, meningiomas. Since meningothelial meningiomas frequently occur in anterior parts of the skull base, the association between tumour localization, size, histological subtype and NF2 status was investigated in a group of 42 sporadic meningiomas. NF2 status was determined by LOH analysis, karyotyping and FISH. Tumour size and site were evaluated by CT scans and MRIs. A strong correlation between tumour localization in the anterior skull base and intact 22q was revealed (p=0.003). On the other hand, tumour localization at the convexity was associated with disruption of NF2 (p=0.023). Furthermore, an association between chromosome 22 status and histological subtype was observed: abnormalities of chromosome 22q were more frequent in transitional and fibrous meningiomas than in the meningothelial variant (p<0.001). Also, the meningothelial meningiomas were more often located in the anterior skull base (p<0.006). Based on these findings, it is concluded that an alternative histogenesis and genetic pathway is likely to exist for meningiomas arising in the anterior skull base.

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Epigenetic modifications have been shown to contribute to the pathogenesis of various cancers including bladder cancer. Hypermethylation in cancer is often found in CGIs in the 5′ regions of genes. These DNA modifications may serve as useful biomarkers, both for diagnostic and prognostic purposes. Although the list of aberrantly methylated genes in cancer is expanding, only a few genes so far were investigated for their usefulness as tumor biomarkers for early diagnosis and risk assessment of bladder cancer. Thus, a large scale (genome wide) screening of aberrant methylation of CGIs is needed to identify bladder-specific epigenetic markers. In this study, we performed a genome wide screening for DNA methylation in different subtypes of bladder cancer using differential methylation hybridization (DMH) coupled with Agilent 244k human CpG island microarrays. We next validated the genome-wide data on a 384-plex custom Illumina Golden Gate Methylation Assay (GGMA), which is based on bisulfite conversion. We found and validated a large number of possible novel epigenetic biomarkers for early detection and prognosis of bladder cancer. We also observed that subgroups of bladder tumors cluster separately due to their different methylation patterns suggesting possible differences in pathogenesis. Our data clearly shown that the adjacent CpG loci within a CGI were co-methylated. In contrast, CGIs neighboring a methylated island were usually not methylated. The data showed no bias toward promoter methylation as the relative proportion of methylated islands in genes was similar to those encompassing promoter regions. We observed that 70% of the methylated genes are downregulated in bladder cancer. Moreover, gene body methylation also seems to be negatively correlated with gene expression. Interestingly, we found an overrepresentation of methylated genes in those genes that are the target of polycomb group protein complexes in embryonic stem cells. Further validation of selected CGIs on a separate group of bladder cancers on a custom Illumina Golden Gate Methylation assay (GGMA) allowed us to confirm 70 % of CGIs differentiating bladder cancers from normal cells, besides validating CGIs discriminating subgroups of bladder tumors. In conclusion, this is the first genome-wide study on bladder cancer which identified potential methylation target genes that provides putative biomarkers that may be correlated with disease course as well as insight into the pathogenesis of bladder cancer subtypes. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4897.