Clinical characteristics, molecular reclassification trajectories and DNA methylation patterns of long- and short-term survivors of WHO grade II and III glioma.

in Journal of neurology by Maximilian J Mair, Annette Leibetseder, Gerwin Heller, Erwin Tomasich, Lisa Müller, Ilka Busse, Adelheid Wöhrer, Barbara Kiesel, Georg Widhalm, Franziska Eckert, Serge Weis, Josef Pichler, Matthias Preusser, Anna S Berghoff

TLDR

  • The study investigated the molecular profile of clinical outliers in diffuse gliomas and identified distinct clinical and molecular features of long-term and short-term survivors.
  • The study highlights the importance of extended molecular workup for diagnosis and further characterization of rare subtypes for optimized treatment strategies and clinical trial planning.

Abstract

The prognosis of diffuse gliomas previously classified as "lower-grade" is heterogeneous and complicates clinical decisions. We aimed to investigate the molecular profile of clinical outliers to gain insight into biological drivers of long and short-term survivors. Here, patients aged ≥ 18 years and diagnosed with diffuse glioma, WHO grade II/2 or III/3 were included. Short-term survivors (STS) were defined as overall survival (OS) < 1 years, and long-term survivors (LTS) as OS > 10 years. DNA methylation profiling was performed using the Illumina EPIC 850k platform. In total, 385 patients (294 LTS, 91 STS) were included. Median overall survival was 234 months (95%CI: 207-248) in LTS and 7.3 months (95%CI: 6.4-8.1) in STS. Compared to STS, LTS were younger, had higher Karnofsky Performance Status, more extensive resections, and lower symptomatic burden (p < 0.001, respectively). Molecular reclassification showed IDH-mutant gliomas in 240/246 (95.5%) LTS and 10/79 (12.7%) STS. Initial diagnosis (tumor type and/or grading) changed in 69/325 (21.2%) patients based on reclassification according to WHO 2016 and in 45/258 (17.4%) as per WHO 2021. DNA methylation analysis indicated two clusters, one with mainly STS (39/41, 95.1%) and heterogeneous IDH-wildtype tumors (cluster A) and one with mainly LTS (82/106, 77.4%) and IDH-mutant tumors (cluster B). Functional enrichment analysis of rare subtypes indicated altered Hippo/Notch and synaptic/neurotransmitter signaling pathway members. LTS and STS show distinct clinical and molecular features, underscoring the importance of extended molecular workup for diagnosis. Further characterization of rare subtypes is needed to optimize treatment strategies and clinical trial planning.

Overview

  • The study aimed to investigate the molecular profile of 'clinical outliers' to gain insight into biological drivers of long-term and short-term survivors of diffuse gliomas.
  • The study included 385 patients with diffuse glioma, WHO grade II/3, aged ≥ 18 years, who were divided into short-term survivors (STS) and long-term survivors (LTS) based on their overall survival.
  • The primary objective of the study was to identify the molecular profile of clinical outliers and to understand the biological drivers of long-term and short-term survivors of diffuse gliomas.

Comparative Analysis & Findings

  • Compared to STS, LTS were younger, had higher Karnofsky Performance Status, more extensive resections, and lower symptomatic burden (p < 0.001, respectively).
  • Molecular reclassification showed IDH-mutant gliomas in 240/246 (95.5%) LTS and 10/79 (12.7%) STS.
  • DNA methylation analysis indicated two clusters, one with mainly STS (39/41, 95.1%) and heterogeneous IDH-wildtype tumors, and one with mainly LTS (82/106, 77.4%) and IDH-mutant tumors.

Implications and Future Directions

  • The study highlights the importance of extended molecular workup for diagnosis, as LTS and STS show distinct clinical and molecular features.
  • Further characterization of rare subtypes is needed to optimize treatment strategies and clinical trial planning.
  • The study emphasizes the need for personalized treatment approaches, taking into account individual patient characteristics and molecular profiles.
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