Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype.

in Acta neuropathologica communications by Arnault Tauziède-Espariat, Lea L Friker, Gunther Nussbaumer, Brigitte Bison, Volodia Dangouloff-Ros, Alice Métais, David Sumerauer, Josef Zamecnik, Martin Benesch, Thomas Perwein, Dannis van Vuurden, Pieter Wesseling, Andrés Morales La Madrid, Maria Luisa Garrè, Manila Antonelli, Felice Giangaspero, Torsten Pietsch, Dominik Sturm, David T W Jones, Stefan M Pfister, Yura Grabovska, Alan Mackay, Chris Jones, Jacques Grill, Yassine Ajlil, André O von Bueren, Michael Karremann, Marion Hoffmann, Christof M Kramm, Robert Kwiecien, David Castel, Gerrit H Gielen, Pascale Varlet

TLDR

  • The study looked at a type of brain tumor called pediatric-type high-grade gliomas (pedHGG) that are H3- and IDH-wildtype. The study found that pedHGG-RTK2A/B tumors are characterized by specific radiological and histo-molecular features and have clinical correlates. The study also found that pedHGG-RTK2A/B tumors are enriched for specific genetic alterations. The study highlights the importance of comprehensive characterization of methylation-based tumors in developing specific and effective therapy concepts for these detrimental tumors. Future research directions could include further characterization of pedHGG-RTK2A/B tumors, including the identification of additional clinical correlates and the development of targeted therapies based on the specific genetic alterations found in these tumors.

Abstract

Diffuse pediatric-type high-grade gliomas (pedHGG), H3- and IDH-wildtype, encompass three main DNA-methylation-based subtypes: pedHGG-MYCN, pedHGG-RTK1A/B/C, and pedHGG-RTK2A/B. Since their first description in 2017 tumors of pedHGG-RTK2A/B have not been comprehensively characterized and clinical correlates remain elusive. In a recent series of pedHGG with a Gliomatosis cerebri (GC) growth pattern, an increased incidence of pedHGG-RTK2A/B (n = 18) was observed. We added 14 epigenetically defined pedHGG-RTK2A/B tumors to this GC series and provided centrally reviewed radiological, histological, and molecular characterization. The final cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 pedHGG-RTK2A (78%) and seven pedHGG-RTK2B (22%) cases. The median age was 11.6 years (range, 4-17) with a median overall survival of 16.0 months (range 10.9-28.2). Seven of 11 of the newly added cases with imaging available showed a GC phenotype at diagnosis or follow-up. PedHGG-RTK2B tumors exhibited frequent bithalamic involvement (6/7, 86%). Central neuropathology review confirmed a diffuse glial neoplasm in all tumors with prominent angiocentric features in both subclasses. Most tumors (24/27 with available data, 89%) diffusely expressed EGFR with focal angiocentric enhancement. PedHGG-RTK2A tumors lacked OLIG2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed this glial transcription factor. ATRX loss occurred in 3/6 pedHGG-RTK2B samples with available data (50%). DNA sequencing (pedHGG-RTK2A: n = 18, pedHGG-RTK2B: n = 5) found EGFR alterations (15/23, 65%; predominantly point mutations) in both subclasses. Mutations in BCOR (14/18, 78%), SETD2 (7/18, 39%), and the hTERT promoter (7/19, 37%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 alterations (4/5, 80%). In conclusion, pedHGG-RTK2A/B tumors are characterized by highly diffuse-infiltrating growth patterns and specific radiological and histo-molecular features. By comprehensively characterizing methylation-based tumors, the chance to develop specific and effective therapy concepts for these detrimental tumors increases.

Overview

  • The study aims to comprehensively characterize pedHGG-RTK2A/B tumors and identify clinical correlates. The study adds 14 epigenetically defined pedHGG-RTK2A/B tumors to a Gliomatosis cerebri (GC) series and provides centrally reviewed radiological, histological, and molecular characterization. The final cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 pedHGG-RTK2A (78%) and seven pedHGG-RTK2B (22%) cases. The median age was 11.6 years (range, 4-17) with a median overall survival of 16.0 months (range 10.9-28.2). The study aims to answer the question of whether pedHGG-RTK2A/B tumors are characterized by specific radiological and histo-molecular features and whether they have clinical correlates.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions or interventions detailed in the study. The study identified an increased incidence of pedHGG-RTK2A/B in the Gliomatosis cerebri (GC) growth pattern. The study also found that pedHGG-RTK2B tumors exhibited frequent bithalamic involvement and central neuropathology review confirmed a diffuse glial neoplasm in all tumors with prominent angiocentric features in both subclasses. The study found that most tumors (24/27 with available data, 89%) diffusely expressed EGFR with focal angiocentric enhancement. The study also found that pedHGG-RTK2A tumors lacked OLIG2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed this glial transcription factor. The study found that ATRX loss occurred in 3/6 pedHGG-RTK2B samples with available data (50%). The study found that DNA sequencing found EGFR alterations (15/23, 65%; predominantly point mutations) in both subclasses. Mutations in BCOR (14/18, 78%), SETD2 (7/18, 39%), and the hTERT promoter (7/19, 37%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 alterations (4/5, 80%). The study found that pedHGG-RTK2A/B tumors are characterized by highly diffuse-infiltrating growth patterns and specific radiological and histo-molecular features.

Implications and Future Directions

  • The study's findings suggest that pedHGG-RTK2A/B tumors are characterized by specific radiological and histo-molecular features and have clinical correlates. The study's findings also suggest that pedHGG-RTK2A/B tumors are enriched for specific genetic alterations. The study's findings highlight the importance of comprehensive characterization of methylation-based tumors in developing specific and effective therapy concepts for these detrimental tumors. Future research directions could include further characterization of pedHGG-RTK2A/B tumors, including the identification of additional clinical correlates and the development of targeted therapies based on the specific genetic alterations found in these tumors.
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