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.

Autor: 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., Obrecht D; Department for Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany., 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., 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., Kloth-Stachnau K; Department for Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany., 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., 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., von Hoff K; Charité-Universitätsmedizin Berlin, Berlin, Germany., Juhnke BO; Department for Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany., 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., 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., 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., 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., 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., 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., 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., Benesch M; Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria., Gerber NU; Department of Oncology, University Children's Hospital, Zurich, Switzerland.; Children's Research Centre, University Children's Hospital, Zurich, Switzerland., 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., 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., 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., 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., Rutkowski S; Department for Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany., 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.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2023 Jan; Vol. 145 (1), pp. 97-112. Date of Electronic Publication: 2022 Dec 02.
DOI: 10.1007/s00401-022-02522-4
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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