Matched Paired Primary and Recurrent Meningiomas Points to Cell-Death Program Contributions to Genomic and Epigenomic Instability along Tumor Progression

SIMPLE SUMMARY: Meningioma (MN) is the most frequent primary brain tumor with a high frequency of recurrences and a lack of objective tools for predicting their prognosis. In this study, we analyzed a careful selection of patients in which both the primary tumor and at least one recurrence were available, allowing us to extend the changes that occur during tumor progression. We developed a histological, genetic, and epigenetic analysis of the samples. Thus, we identified markers of quick recurrence, increased tumor instability by copy number alterations, and the accumulation of epigenetic changes during tumor progression. Interestingly, the genes involved seemed to be randomly distributed along the genome but eventually suggest a common impact on cell-death programs such as apoptosis and autophagy. ABSTRACT: Meningioma (MN) is an important cause of disability, and predictive tools for estimating the risk of recurrence are still scarce. The need for objective and cost-effective techniques addressed to this purpose is well known. In this study, we present methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a friendly method for deepening the understanding of the mechanisms underlying meningioma progression. A large follow-up allowed us to obtain 50 samples, which included the primary tumor of 20 patients in which half of them are suffering one recurrence and the other half are suffering more than one. We histologically characterized the samples and performed MS-MLPA assays validated by FISH to assess their copy number alterations (CNA) and epigenetic status. Interestingly, we determined the increase in tumor instability with higher values of CNA during the progression accompanied by an increase in epigenetic damage. We also found a loss of HIC1 and the hypermethylation of CDKN2B and PTEN as independent prognostic markers. Comparison between grade 1 and higher primary MN’s self-evolution pointed to a central role of GSTP1 in the first stages of the disease. Finally, a high rate of alterations in genes that are related to apoptosis and autophagy, such as DAPK1, PARK2, BCL2, FHIT, or VHL, underlines an important influence on cell-death programs through different pathways.