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

Gunther Nussbaumer; Martin Benesch; Yura Grabovska; Alan Mackay; David Castel; Jacques Grill; Marta M Alonso; Manila Antonelli; Simon Bailey; Joshua N Baugh; Veronica Biassoni; Mirjam Blattner-Johnson; Alberto Broniscer; Andrea Carai; Giovanna Stefania Colafati; Niclas Colditz; Selim Corbacioglu; Shauna Crampsie; Natacha Entz-Werle; Matthias Eyrich; Lea L Friker; Michael C Frühwald; Maria Luisa Garrè; Nicolas U Gerber; Felice Giangaspero; Maria J Gil-da-Costa; Norbert Graf; Darren Hargrave; Peter Hauser; Ulrich Herrlinger; Marion Hoffmann; Esther Hulleman; Elisa Izquierdo; Sandra Jacobs; Michael Karremann; Antonis Kattamis; Rejin Kebudi; Rolf-Dieter Kortmann; Robert Kwiecien; Maura Massimino; Angela Mastronuzzi; Evelina Miele; Giovanni Morana; Claudia M Noack; Virve Pentikainen; Thomas Perwein; Stefan M Pfister; Torsten Pietsch; Kleoniki Roka; Sabrina Rossi; Stefan Rutkowski; Elisabetta Schiavello; Clemens Seidel; Jaroslav Štěrba; Dominik Sturm; David Sumerauer; Anna Tacke; Sara Temelso; Chiara Valentini; Dannis van Vuurden; Pascale Varlet; Sophie E M Veldhuijzen van Zanten; Maria Vinci; André O von Bueren; Monika Warmuth-Metz; Pieter Wesseling; Maria Wiese; Johannes E A Wolff; Josef Zamecnik; Andrés Morales La Madrid; Brigitte Bison; Gerrit H Gielen; David T W Jones; Chris Jones; Christof M Kramm

doi:10.1093/neuonc/noae080

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

Gunther Nussbaumer (Corresponding Author)
, Martin Benesch
, Yura Grabovska
, Alan Mackay
, David Castel
, Jacques Grill
, Marta M Alonso
, Manila Antonelli
, Simon Bailey
, Joshua N Baugh
, Veronica Biassoni
, Mirjam Blattner-Johnson
, Alberto Broniscer
, Andrea Carai
, Giovanna Stefania Colafati
, Niclas Colditz
, Selim Corbacioglu
, Shauna Crampsie
, Natacha Entz-Werle
, Matthias Eyrich

Lea L Friker, Michael C Frühwald, Maria Luisa Garrè, Nicolas U Gerber, Felice Giangaspero, Maria J Gil-da-Costa, Norbert Graf, Darren Hargrave, Peter Hauser, Ulrich Herrlinger, Marion Hoffmann, Esther Hulleman, Elisa Izquierdo, Sandra Jacobs, Michael Karremann, Antonis Kattamis, Rejin Kebudi, Rolf-Dieter Kortmann, Robert Kwiecien, Maura Massimino, Angela Mastronuzzi, Evelina Miele, Giovanni Morana, Claudia M Noack, Virve Pentikainen, Thomas Perwein, Stefan M Pfister, Torsten Pietsch, Kleoniki Roka, Sabrina Rossi, Stefan Rutkowski, Elisabetta Schiavello, Clemens Seidel, Jaroslav Štěrba, Dominik Sturm, David Sumerauer, Anna Tacke, Sara Temelso, Chiara Valentini, Dannis van Vuurden, Pascale Varlet, Sophie E M Veldhuijzen van Zanten, Maria Vinci, André O von Bueren, Monika Warmuth-Metz, Pieter Wesseling, Maria Wiese, Johannes E A Wolff, Josef Zamecnik, Andrés Morales La Madrid, Brigitte Bison, Gerrit H Gielen, David T W Jones, Chris Jones, Christof M Kramm (Corresponding Author)

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

Abstract

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).

Original language	English
Pages (from-to)	1723-1737
Number of pages	15
Journal	Neuro-Oncology
Volume	26
Issue number	9
DOIs	https://doi.org/10.1093/neuonc/noae080
Publication status	Published - 5 Sept 2024
Externally published	Yes

Keywords*

Humans
Child
Male
Neoplasms, Neuroepithelial/pathology
Female
Adolescent
Retrospective Studies
Prognosis
Child, Preschool
Brain Neoplasms/genetics
Glioma/genetics
Phenotype
Survival Rate
DNA Methylation
Infant
Biomarkers, Tumor/genetics
Mutation
Follow-Up Studies
Neoplasm Grading

Field of Science*

3.2 Clinical medicine

Publication Type*

1.1. Scientific article indexed in Web of Science and/or Scopus database

Access to Document

10.1093/neuonc/noae080Licence: CC BY

Cite this

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., ... Kramm, C. M. (2024). Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile. Neuro-Oncology, 26(9), 1723-1737. https://doi.org/10.1093/neuonc/noae080

@article{bc6b552f682b43b1adfa4528e5f966e1,

title = "Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile",

abstract = "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).",

keywords = "Humans, Child, Male, Neoplasms, Neuroepithelial/pathology, Female, Adolescent, Retrospective Studies, Prognosis, Child, Preschool, Brain Neoplasms/genetics, Glioma/genetics, Phenotype, Survival Rate, DNA Methylation, Infant, Biomarkers, Tumor/genetics, Mutation, Follow-Up Studies, Neoplasm Grading",

author = "Gunther Nussbaumer and Martin Benesch and Yura Grabovska and Alan Mackay and David Castel and Jacques Grill and Alonso, \{Marta M\} and Manila Antonelli and Simon Bailey and Baugh, \{Joshua N\} and Veronica Biassoni and Mirjam Blattner-Johnson and Alberto Broniscer and Andrea Carai and Colafati, \{Giovanna Stefania\} and Niclas Colditz and Selim Corbacioglu and Shauna Crampsie and Natacha Entz-Werle and Matthias Eyrich and Friker, \{Lea L\} and Fr{\"u}hwald, \{Michael C\} and Garr{\`e}, \{Maria Luisa\} and Gerber, \{Nicolas U\} and Felice Giangaspero and Gil-da-Costa, \{Maria J\} and Norbert Graf and Darren Hargrave and Peter Hauser and Ulrich Herrlinger and Marion Hoffmann and Esther Hulleman and Elisa Izquierdo and Sandra Jacobs and Michael Karremann and Antonis Kattamis and Rejin Kebudi and Rolf-Dieter Kortmann and Robert Kwiecien and Maura Massimino and Angela Mastronuzzi and Evelina Miele and Giovanni Morana and Noack, \{Claudia M\} and Virve Pentikainen and Thomas Perwein and Pfister, \{Stefan M\} and Torsten Pietsch and Kleoniki Roka and Sabrina Rossi and Stefan Rutkowski and Elisabetta Schiavello and Clemens Seidel and Jaroslav {\v S}t{\v e}rba and Dominik Sturm and David Sumerauer and Anna Tacke and Sara Temelso and Chiara Valentini and \{van Vuurden\}, Dannis and Pascale Varlet and \{Veldhuijzen van Zanten\}, \{Sophie E M\} and Maria Vinci and \{von Bueren\}, \{Andr{\'e} O\} and Monika Warmuth-Metz and Pieter Wesseling and Maria Wiese and Wolff, \{Johannes E A\} and Josef Zamecnik and \{Morales La Madrid\}, Andr{\'e}s and Brigitte Bison and Gielen, \{Gerrit H\} and Jones, \{David T W\} and Chris Jones and Kramm, \{Christof M\}",

note = "{\textcopyright} The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.",

year = "2024",

month = sep,

day = "5",

doi = "10.1093/neuonc/noae080",

language = "English",

volume = "26",

pages = "1723--1737",

journal = "Neuro-Oncology",

issn = "1522-8517",

publisher = "Oxford University Press",

number = "9",

}

Nussbaumer, G, Benesch, M, Grabovska, Y, Mackay, A, Castel, D, Grill, J, Alonso, MM, Antonelli, M, Bailey, S, Baugh, JN, Biassoni, V, Blattner-Johnson, M, Broniscer, A, Carai, A, Colafati, GS, Colditz, N, Corbacioglu, S, Crampsie, S, Entz-Werle, N, Eyrich, M, Friker, LL, Frühwald, MC, Garrè, ML, Gerber, NU, Giangaspero, F, Gil-da-Costa, MJ, 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, A, Miele, E, Morana, G, Noack, CM, Pentikainen, V, Perwein, T, Pfister, SM, Pietsch, T, Roka, K, Rossi, S, Rutkowski, S, Schiavello, E, Seidel, C, Štěrba, J, Sturm, D, Sumerauer, D, Tacke, A, Temelso, S, Valentini, C, van Vuurden, D, Varlet, P, Veldhuijzen van Zanten, SEM, Vinci, M, von Bueren, AO, Warmuth-Metz, M, Wesseling, P, Wiese, M, Wolff, JEA, Zamecnik, J, Morales La Madrid, A, Bison, B, Gielen, GH, Jones, DTW, Jones, C & Kramm, CM 2024, 'Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile', Neuro-Oncology, vol. 26, no. 9, pp. 1723-1737. https://doi.org/10.1093/neuonc/noae080

TY - JOUR

T1 - Gliomatosis cerebri in children

T2 - A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile

AU - Nussbaumer, Gunther

AU - Benesch, Martin

AU - Grabovska, Yura

AU - Mackay, Alan

AU - Castel, David

AU - Grill, Jacques

AU - Alonso, Marta M

AU - Antonelli, Manila

AU - Bailey, Simon

AU - Baugh, Joshua N

AU - Biassoni, Veronica

AU - Blattner-Johnson, Mirjam

AU - Broniscer, Alberto

AU - Carai, Andrea

AU - Colafati, Giovanna Stefania

AU - Colditz, Niclas

AU - Corbacioglu, Selim

AU - Crampsie, Shauna

AU - Entz-Werle, Natacha

AU - Eyrich, Matthias

AU - Friker, Lea L

AU - Frühwald, Michael C

AU - Garrè, Maria Luisa

AU - Gerber, Nicolas U

AU - Giangaspero, Felice

AU - Gil-da-Costa, Maria J

AU - Graf, Norbert

AU - Hargrave, Darren

AU - Hauser, Peter

AU - Herrlinger, Ulrich

AU - Hoffmann, Marion

AU - Hulleman, Esther

AU - Izquierdo, Elisa

AU - Jacobs, Sandra

AU - Karremann, Michael

AU - Kattamis, Antonis

AU - Kebudi, Rejin

AU - Kortmann, Rolf-Dieter

AU - Kwiecien, Robert

AU - Massimino, Maura

AU - Mastronuzzi, Angela

AU - Miele, Evelina

AU - Morana, Giovanni

AU - Noack, Claudia M

AU - Pentikainen, Virve

AU - Perwein, Thomas

AU - Pfister, Stefan M

AU - Pietsch, Torsten

AU - Roka, Kleoniki

AU - Rossi, Sabrina

AU - Rutkowski, Stefan

AU - Schiavello, Elisabetta

AU - Seidel, Clemens

AU - Štěrba, Jaroslav

AU - Sturm, Dominik

AU - Sumerauer, David

AU - Tacke, Anna

AU - Temelso, Sara

AU - Valentini, Chiara

AU - van Vuurden, Dannis

AU - Varlet, Pascale

AU - Veldhuijzen van Zanten, Sophie E M

AU - Vinci, Maria

AU - von Bueren, André O

AU - Warmuth-Metz, Monika

AU - Wesseling, Pieter

AU - Wiese, Maria

AU - Wolff, Johannes E A

AU - Zamecnik, Josef

AU - Morales La Madrid, Andrés

AU - Bison, Brigitte

AU - Gielen, Gerrit H

AU - Jones, David T W

AU - Jones, Chris

AU - Kramm, Christof M

PY - 2024/9/5

Y1 - 2024/9/5

N2 - 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).

AB - 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).

KW - Humans

KW - Child

KW - Male

KW - Neoplasms, Neuroepithelial/pathology

KW - Female

KW - Adolescent

KW - Retrospective Studies

KW - Prognosis

KW - Child, Preschool

KW - Brain Neoplasms/genetics

KW - Glioma/genetics

KW - Phenotype

KW - Survival Rate

KW - DNA Methylation

KW - Infant

KW - Biomarkers, Tumor/genetics

KW - Mutation

KW - Follow-Up Studies

KW - Neoplasm Grading

UR - https://www.scopus.com/pages/publications/85199676724

U2 - 10.1093/neuonc/noae080

DO - 10.1093/neuonc/noae080

M3 - Article

C2 - 38717379

SN - 1522-8517

VL - 26

SP - 1723

EP - 1737

JO - Neuro-Oncology

JF - Neuro-Oncology

IS - 9

ER -

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

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Keywords*

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