Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecul profile

Nussbaumer, G.; Benesch, M.; Grabovska, Y.; Mackay, A.; Castel, D.; Grill, J.; Alonso, M. M.; Antonelli, M.; Bailey, S.; Baugh, J. N.; Biassoni, V.; Blattner-Johnson, M.; Broniscer, A.; Carai, A.; Colafati, G. S.; Colditz, N.; Corbacioglu, S.; Crampsie, S.; Entz-Werle, N.; Eyrich, M.; Friker, L. L.; Fruhwald, M. C.; Garre, M. L.; Gerber, N. U.; Giangaspero, F.; Gil-Da-Costa, M. J.; Graf, N.; Hargrave, D.; Hauser, P.; Herrlinger, U.; Hoffmann, M.; Hulleman, E.; Izquierdo, E.; Jacobs, S.; Karremann, M.; Kattamis, A.; Kebudi, R.; Kortmann, R. -D.; Kwiecien, R.; Massimino, M.; Mastronuzzi, Angela; Miele, E.; Morana, G.; Noack, C. M.; Pentikainen, V.; Perwein, T.; Pfister, S. M.; Pietsch, T.; Roka, K.; Rossi, S.; Rutkowski, S.; Schiavello, E.; Seidel, C.; Sterba, J.; Sturm, D.; Sumerauer, D.; Tacke, A.; Temelso, S.; Valentini, C.; Van Vuurden, D.; Varlet, P.; Veldhuijzen Van Zanten, S. E. M.; Vinci, M.; Von Bueren, A. O.; Warmuth-Metz, M.; Wesseling, P.; Wiese, M.; Wolff, J. E. A.; Zamecnik, J.; La Madrid, A. M.; Bison, B.; Gielen, G. H.; Jones, D. T. W.; Jones, C.; Kramm, C. M.

doi:10.1093/neuonc/noae080

Background. The term gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features could not be established. Methods. We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization. Results. Median overall survival (OS) was 15.5 months (interquartile range, 10.9–27.7) with a 2-year survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2–55.7); grade III: 15.9 months (11.4–26.3); grade IV: 10.4 months (8.8–14.4). By DNA methylation profiling (n = 49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wild-type (n = 31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n = 19), pedHGG_A/B (n = 6), and pedHGG_MYCN (n = 5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wild-type subgroup, recurrent alterations in EGFR (n = 10) and BCOR (n = 9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wild-type subgroup TP53 alterations had a significant negative effect on OS. Conclusions. Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_ RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements).

Nussbaumer, G., Benesch, M., Grabovska, Y., Mackay, A., Castel, D., Grill, J., Alonso, M. M., Antonelli, M., Bailey, S., Baugh, J. N., Biassoni, V., Blattner-Johnson, M., Broniscer, A., Carai, A., Colafati, G. S., Colditz, N., Corbacioglu, S., Crampsie, S., Entz-Werle, N., Eyrich, M., Friker, L. L., Fruhwald, M. C., Garre, M. L., Gerber, N. U., Giangaspero, F., Gil-Da-Costa, M. J., Graf, N., Hargrave, D., Hauser, P., Herrlinger, U., Hoffmann, M., Hulleman, E., Izquierdo, E., Jacobs, S., Karremann, M., Kattamis, A., Kebudi, R., Kortmann, R. -., Kwiecien, R., Massimino, M., Mastronuzzi, A., Miele, E., Morana, G., Noack, C. M., Pentikainen, V., Perwein, T., Pfister, S. M., Pietsch, T., Roka, K., Rossi, S., Rutkowski, S., Schiavello, E., Seidel, C., Sterba, J., Sturm, D., Sumerauer, D., Tacke, A., Temelso, S., Valentini, C., Van Vuurden, D., Varlet, P., Veldhuijzen Van Zanten, S. E. M., Vinci, M., Von Bueren, A. O., Warmuth-Metz, M., Wesseling, P., Wiese, M., Wolff, J. E. A., Zamecnik, J., La Madrid, A. M., Bison, B., Gielen, G. H., Jones, D. T. W., Jones, C., Kramm, C. M., Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecul profile, <<NEURO-ONCOLOGY>>, 2024; 26 (9): 1723-1737. [doi:10.1093/neuonc/noae080] [https://hdl.handle.net/10807/329568]