Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma

Abstract

Meningioma is the most common primary brain tumor and carries a substantial risk of local recurrence. Methylation profiles of meningioma and their clinical implications are not well understood. We hypothesized that aggressive meningiomas have unique DNA methylation patterns that could be used to better stratify patient management. Samples (n=140) were profiled using the Illumina HumanMethylation450 BeadChip. Unsupervised modeling on a training set (n=89) identified 2 molecular methylation subgroups of meningioma (MM) with significantly different recurrence free survival (RFS) times between the groups: a prognostically unfavorable subgroup (MM-UNFAV) and a prognostically favorable subgroup (MM-FAV). This finding was validated in the remaining 51 samples and led to a baseline meningioma methylation classifier (bMMC) defined by 283 CpG loci (283-bMMC). To further optimize a recurrence predictor, probes subsumed within the baseline classifier were subject to additional modeling using a similar training/validation approach, leading to a 64-CpG loci meningioma methylation predictor (64-MMP). After adjustment for relevant clinical variables [WHO grade, mitotic index, Simpson grade, sex, location, and copy number aberrations (CNA)] multivariable analyses for RFS showed that the baseline methylation classifier was not significant (p=0.0793). The methylation predictor however was significantly associated with tumor recurrence (p<0.0001). CNA were extracted from the 450k intensity profiles. Tumor samples in the MM-UNFAV subgroup showed an overall higher proportion of CNAs compared to the MM-FAV subgroup tumors and the CNAs were complex in nature. CNAs in the MM-UNFAV subgroup included recurrent losses of 1p, 6q, 14q and 18q, and gain of 1q, all of which were previously identified as indicators of poor outcome. In conclusion, our analyses demonstrate robust DNA methylation signatures in meningioma that correlate with CNAs and stratify patients by recurrence risk.

Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors

“…There are two limitations to our study. Several previous studies have explored DNA methylation profiling (14,(19)(20)(21), and it would be ideal to compare our classification system with that proposed by Sahm et al by performing RNA-seq and methylation profiling on the same samples (14). (Methylation and expression may (45) or may not (46) correlate.)…”

“…Bi et al found that grade III tumors are less likely to have TRAF7, KL4, AKT1, or SMO mutations but more likely to show genomic instability (copy number variation or CNV) (18). Vasudevan et al sought targetable pathways in high-grade meningiomas and found that high FOXM1 expression is associated with poor clinical outcomes (19); this is one of several studies showing that DNA methylation profiles have clinical relevance (14,(19)(20)(21).…”

Biomarkers in tumors of the central nervous system – a review

“…A study by Olar et al. also found that DNA methylation analysis of meningiomas reliably identified patients with risk of tumor recurrence. Katz et al.…”

“…Approximately 20% meningioma patients have an aggressive clinical course with tumor recurrence and progressive disease (1,157,158). Extent of tumor resection and WHO grade are the most important clinical factors for predicting outcome (155,(159)(160)(161). However, currently the risk stratification of meningioma patients is imprecise as some patients with WHO grade I tumors experience early recurrence and an aggressive clinical course, whereas only 29-52% of WHO grade II tumors recur (1,161).…”

“…Extent of tumor resection and WHO grade are the most important clinical factors for predicting outcome (155,(159)(160)(161). However, currently the risk stratification of meningioma patients is imprecise as some patients with WHO grade I tumors experience early recurrence and an aggressive clinical course, whereas only 29-52% of WHO grade II tumors recur (1,161). Mutation in the NF2 gene and loss of chromosome 22 are the most frequent genetic alteration in meningiomas (1).…”