TERT promoter mutation and H3K27me3 trimethylation loss as focal molecular markers in meningioma aggressiveness
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Abstract
Biomarkers to identify high-grade meningiomas have finally been added to the recent 2021 edition of the World Health Organization (WHO) grading scheme. Among them, are the well-known telomerase reverse transcriptase promoter (TERTp) mutation and the recently emerged epigenetic marker, trimethylation of lysine 27 of histone 3 (H3K27me3). Although the presence of TERTp is now associated with WHO grade 3 meningiomas and the loss of trimethylation of H3K27me3 is implicated with potentially worse prognosis, the question remains as to their ability to predict an event rather than an observed association. Furthermore, the standards for H3K27me3 immunohistochemistry (IHC) in meningiomas have not been set and have led to inconsistencies in reporting. To address these critical clinical concerns, I set out to investigate the prevalence of TERTp mutations in a cohort of suspected high-risk meningiomas through Sanger sequencing. I also conducted a meta-analysis of all H3K27me3 publications to qualify the current assessment of H3K27me3 trimethylation loss as a predictor of tumor aggressiveness. Due to complications with the quality of purified DNA from FFPE tissue, I was unable to obtain satisfactory sequencing results to assess the prevalence of TERTp mutation in my cohort. I did, however, develop an optimized DNA purification protocol for FFPE tissues for future research purposes. The pooled data on H3K27me3 did confirm a significant association between the loss of H3K27me3 trimethylation and more aggressive tumors (p<0.0001). I also determined that by separating the pooled data on H3K27me3 loss into two groups defined by the inclusion of a tissue age cutoff for staining, the group that excluded tissue sections >5 years old resulted in significantly higher rates of H3K27me3 loss, implying tissue age and quality had a significant effect on the staining for H3K27me3 loss in meningiomas. Although H3K27me3 is associated substantially with meningiomas of more aggressive nature and thus a higher likelihood of recurrence, several criteria must be met first to standardize the process to ensure accuracy in reporting and ease of implementation into standard clinical workups.