Identification of low and very high-risk patients with non-WNT/non-SHH medulloblastoma by improved clinico-molecular stratification of the HIT2000 and I-HIT-MED cohorts.

Humans Medulloblastoma Cerebellar Neoplasms / genetics Chromosome Aberrations Risk Microarray Analysis
Group 3/4 Medulloblastoma Non-WNT/non-SHH Risk stratification

Journal

Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041

Informations de publication

Date de publication:
01 2023
Historique:
received: 12 07 2022
accepted: 14 11 2022
revised: 14 11 2022
pubmed: 3 12 2022
medline: 5 1 2023
entrez: 2 12 2022
Statut: ppublish

Résumé

Molecular groups of medulloblastoma (MB) are well established. Novel risk stratification parameters include Group 3/4 (non-WNT/non-SHH) methylation subgroups I-VIII or whole-chromosomal aberration (WCA) phenotypes. This study investigates the integration of clinical and molecular parameters to improve risk stratification of non-WNT/non-SHH MB. Non-WNT/non-SHH MB from the HIT2000 study and the HIT-MED registries were selected based on availability of DNA-methylation profiling data. MYC or MYCN amplification and WCA of chromosomes 7, 8, and 11 were inferred from methylation array-based copy number profiles. In total, 403 non-WNT/non-SHH MB were identified, 346/403 (86%) had a methylation class family Group 3/4 methylation score (classifier v11b6) ≥ 0.9, and 294/346 (73%) were included in the risk stratification modeling based on Group 3 or 4 score (v11b6) ≥ 0.8 and subgroup I-VIII score (mb_g34) ≥ 0.8. Group 3 MB (5y-PFS, survival estimation ± standard deviation: 41.4 ± 4.6%; 5y-OS: 48.8 ± 5.0%) showed poorer survival compared to Group 4 (5y-PFS: 68.2 ± 3.7%; 5y-OS: 84.8 ± 2.8%). Subgroups II (5y-PFS: 27.6 ± 8.2%) and III (5y-PFS: 37.5 ± 7.9%) showed the poorest and subgroup VI (5y-PFS: 76.6 ± 7.9%), VII (5y-PFS: 75.9 ± 7.2%), and VIII (5y-PFS: 66.6 ± 5.8%) the best survival. Multivariate analysis revealed subgroup in combination with WCA phenotype to best predict risk of progression and death. The integration of clinical (age, M and R status) and molecular (MYC/N, subgroup, WCA phenotype) variables identified a low-risk stratum with a 5y-PFS of 94 ± 5.7 and a very high-risk stratum with a 5y-PFS of 29 ± 6.1%. Validation in an international MB cohort confirmed the combined stratification scheme with 82.1 ± 6.0% 5y-PFS in the low and 47.5 ± 4.1% in very high-risk groups, and outperformed the clinical model. These newly identified clinico-molecular low-risk and very high-risk strata, accounting for 6%, and 21% of non-WNT/non-SHH MB patients, respectively, may improve future treatment stratification.

Identifiants

DOI: 10.1007/s00401-022-02522-4 PMID: 36459208 PMC: PMC9807480
pubmed: 36459208
doi: 10.1007/s00401-022-02522-4
pii: 10.1007/s00401-022-02522-4
pmc: PMC9807480
doi:

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

97-112

Informations de copyright

© 2022. The Author(s).

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Auteurs

Martin Mynarek (M)

Department for Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany. m.mynarek@uke.de.
Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. m.mynarek@uke.de.

Denise Obrecht (D)

Department for Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Martin Sill (M)

Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

Dominik Sturm (D)

Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

Katja Kloth-Stachnau (K)

Department for Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Florian Selt (F)

Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

Jonas Ecker (J)

Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

Katja von Hoff (K)

Charité-Universitätsmedizin Berlin, Berlin, Germany.

Björn-Ole Juhnke (BO)

Department for Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Tobias Goschzik (T)

Institute of Neuropathology, Brain Tumor Reference Center of the German Society for Neuropathology and Neuroanatomy (DGNN), University of Bonn Medical Center, Bonn, Germany.

Torsten Pietsch (T)

Institute of Neuropathology, Brain Tumor Reference Center of the German Society for Neuropathology and Neuroanatomy (DGNN), University of Bonn Medical Center, Bonn, Germany.

Michael Bockmayr (M)

Department for Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Charité-Universitätsmedizin Berlin, Berlin, Germany.
Research Institute Children's Cancer Center Hamburg, Hamburg, Germany.

Marcel Kool (M)

Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Andreas von Deimling (A)

Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Olaf Witt (O)

Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

Ulrich Schüller (U)

Department for Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
Research Institute Children's Cancer Center Hamburg, Hamburg, Germany.
Department of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Martin Benesch (M)

Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria.

Nicolas U Gerber (NU)

Department of Oncology, University Children's Hospital, Zurich, Switzerland.
Children's Research Centre, University Children's Hospital, Zurich, Switzerland.

Felix Sahm (F)

Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

David T W Jones (DTW)

Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

Andrey Korshunov (A)

Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Stefan M Pfister (SM)

Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.

Stefan Rutkowski (S)

Department for Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Till Milde (T)

Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. t.milde@kitz-heidelberg.de.
Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany. t.milde@kitz-heidelberg.de.
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany. t.milde@kitz-heidelberg.de.
ORCID: 0000-0002-7267-1052

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Identification of low and very high-risk...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroépitheliales › Tumeurs neuroectodermiques primitives › Médulloblastome › Identification of low and very high-risk...
questionsmedicales.fr › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › Tumeurs sous-tentorielles › Tumeurs du cervelet › Identification of low and very high-risk...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Aberrations des chromosomes › Identification of low and very high-risk...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Risque › Identification of low and very high-risk...
questionsmedicales.fr › Techniques d'investigation › Procédures d'analyse sur micropuce › Analyse sur microréseau › Identification of low and very high-risk...