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Mynarek, Martin; Obrecht, Denise; Sill, Martin; Sturm, Dominik; Kloth-Stachnau, Katja; Selt, Florian; Ecker, Jonas; von Hoff, Katja; Juhnke, Björn-Ole; Goschzik, Tobias; Pietsch, Torsten; Bockmayr, Michael; Kool, Marcel; von Deimling, Andreas; Witt, Olaf; Schüller, Ulrich; Benesch, Martin; Gerber, Nicolas U.; Sahm, Felix; Jones, David T. W.; Korshunov, Andrey; Pfister, Stefan M.; Rutkowski, Stefan; Milde, Till

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

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  • Medientyp: E-Artikel
  • Titel: 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
  • Beteiligte: Mynarek, Martin; Obrecht, Denise; Sill, Martin; Sturm, Dominik; Kloth-Stachnau, Katja; Selt, Florian; Ecker, Jonas; von Hoff, Katja; Juhnke, Björn-Ole; Goschzik, Tobias; Pietsch, Torsten; Bockmayr, Michael; Kool, Marcel; von Deimling, Andreas; Witt, Olaf; Schüller, Ulrich; Benesch, Martin; Gerber, Nicolas U.; Sahm, Felix; Jones, David T. W.; Korshunov, Andrey; Pfister, Stefan M.; Rutkowski, Stefan; Milde, Till
  • Erschienen: Springer Science and Business Media LLC, 2023
  • Erschienen in: Acta Neuropathologica
  • Sprache: Englisch
  • DOI: 10.1007/s00401-022-02522-4
  • ISSN: 0001-6322; 1432-0533
  • Schlagwörter: Cellular and Molecular Neuroscience ; Neurology (clinical) ; Pathology and Forensic Medicine
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>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. <jats:italic>MYC</jats:italic> or <jats:italic>MYCN</jats:italic> 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.</jats:p>