P02.15.A PRONEURAL, CLASSICAL AND MESENCHYMAL PROTEIN SIGNATURES LACK PROGNOSTIC VALUE IN WHO 2021 ADULT TYPE DIFFUSE LOWER-GRADE GLIOMAS

Abstract

Abstract BACKGROUND Mesenchymal transformation in glioblastomas is associated with therapy resistance and increased aggressiveness. In WHO 2021-defined adult-type diffuse gliomas of lower grade (dLGG), the transition between phenotypic states, has not been studied. Most reports correlating proneural, classical or mesenchymal signatures with outcome in dLGG were made prior to the WHO 2021 classification. Here, we set out to investigate if phenotype as well as the transition of phenotype predicted survival in a clinical cohort of WHO 2021 defined dLGGs. MATERIAL AND METHODS We used a TMA-based approach and five immunohistochemical markers (EGFR, p53, MERTK, CD44 and OLIG2) to examine 183 primary and 49 recurrent tumors from patients with previously diagnosed dLGG. Of the 49 recurrent tumors, nine tumors relapsed a second time, and one a third time. RESULTS In total, 71.0% of all tumors could be subtyped into proneural, classical or mesenchymal. Proneural was the predominant subtype among IDH-mut tumors (78.5%), while in IDH-wt tumors mesenchymal was more common (63.6%). A significant difference in survival was found between subtypes (proneural, classical and mesenchymal) in the total cohort (p<0.001), but not when molecularly stratified (IDH-mut: p=0.220, IDH-wt: p=0.623). Upon relapse, proneural signature was retained in 66.7% of the proneural IDH-mut dLGGs (n=21), whereas IDH-wt tumors (n=10) mainly retained or gained mesenchymal phenotype. There was no significant difference in survival between IDH-mut gliomas remaining proneural and those switching to mesenchymal signature (p=0.347). CONCLUSION Subtyping into proneural, classical and mesenchymal phenotypes by five immunohistochemical markers, was possible for the majority of tumors, but statistical significance between phenotypes and survival was lost after molecular stratification according to the WHO 2021 criteria. IDH-mut tumors mainly remained proneural at recurrence, while IDH-wt tumors mostly retained or gained mesenchymal phenotype. This phenotypic shift, which in glioblastoma is associated with increased aggressiveness, did not affect survival. Sample sizes were, however, too small to draw any firm conclusions on whether this negative finding is due to lack of statistical power or reflects a true biological difference from glioblastomas.