DNA methylation subclasses predict the benefit from gross total tumor resection in IDH-wildtype glioblastoma patients

Abstract

Background DNA methylation-based tumor classification allows an enhanced distinction into subgroups of glioblastoma. However, the clinical benefit of DNA methylation-based stratification of glioblastomas remains inconclusive. Methods Multicentric cohort study including 430 patients with newly diagnosed glioblastoma subjected to global DNA methylation profiling. Outcome measures included overall survival (OS), progression-free survival (PFS), prognostic relevance of EOR and MGMT promoter methylation status as well as surgical benefit for recurrent glioblastoma. Results 345 patients (80.2%) fulfilled the inclusion criteria. DNA methylation subclasses RTK I, RTK II, and mesenchymal (MES) revealed no significant survival differences (p = 0.06). 305 Patients receiving combined adjuvant therapy (RTK I: Ref.; RTK II: HR 0.9 [95% CI, 0.64-1.28]; p = 0.56; MES: 0.69 [0.47-1.02]; p = 0.06). RTK I (GTR/near GTR: Ref.; PR: HR 2.87 [95% CI, 1.36-6.08]; p < 0.01) or RTK II (GTR/near GTR: Ref.; PR: HR 5.09 [95% CI, 2.80-9.26]; p < 0.01) tumors who underwent gross-total resection (GTR) or near GTR had a longer OS and PFS than partially resected patients. The MES subclass showed no survival benefit for a maximized EOR (GTR/near GTR: Ref.; PR: HR 1.45 [95% CI, 0.68-3.09]; p = 0.33). Therapy response-predictive value of MGMT promoter methylation was evident for RTK I (HR 0.37 [95% CI, 0.19-0.71]; p < 0.01) and RTK II (HR 0.56 [95% CI, 0.34-0.91]; p = 0.02) but not the MES subclass (HR 0.52 [95% CI, 0.27-1.02]; p = 0.06). For local recurrence (n=112), re-resection conveyed a progression-to-overall survival (POS) benefit (p < 0.01), which was evident in RTK I (p = 0.03) and RTK II (p < 0.01) tumors, but not in MES tumors (p = 0.33). Conclusion We demonstrate a survival benefit from maximized EOR for newly diagnosed and recurrent glioblastomas of the RTK I and RTK II but not the MES subclass. Hence, it needs to be debated whether the MES subclass should be treated with maximal surgical resection, especially when located in eloquent areas and at time of recurrence.

A multi-omics analysis-based model to predict the prognosis of low-grade gliomas

“…DNA methylation is a major epigenetic signature occurring in early cancer events, which exhibits great potential in the risk assessment, early identification and prognosis prediction of various cancers 27 – 29 . We showed 2077 genes were more methylated and 299 were less methylated in recurrent vs. primary samples, and that the differential methylation was mainly within genes, which might suggest the epigenetic alterations in recurrence of LGG.…”

DistSNE: Distributed computing and online visualization of DNA methylation‐based central nervous system tumor classification

“…Importantly, DistSNE maintained classification accuracy equivalent to that of a centralized method while preserving data privacy in line with previous studies on other medical datasets [ 22 , 23 ]. The increased resolution could lead to the discovery of novel clusters and a deeper understanding of tumor biology [ 24 , 25 , 26 , 27 ]. This suggests that our federated DistSNE computation approach may be beneficial in large‐scale studies and consortium‐based research projects where data privacy and protection, became a major concern in the era of big data especially in medical research [ 28 , 29 ].…”

AI-based molecular classification of diffuse gliomas using rapid, label-free optical imaging

“…AI-based molecular classification of diffuse gliomas Streamlining molecular classification could also have an immediate impact on the surgical care of brain tumor patients. A growing body of evidence supports that surgical goals should be tailored based on molecular subgroups [40][41][42][43]. Notably, extent of resection carries a greater impact on survival in molecular astrocytomas (IDH-mutant, 1p19q-intact) than oligodendrogliomas (IDH-mutant, 1p19q-codeleted).…”