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

• Published in: Acta neuropathologica 2023-01, Vol.145 (1), p.97-112
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Cerebellar Neoplasms - genetics; Chromosome Aberrations; Chromosomes; Copy number; DNA fingerprinting; DNA methylation; Humans; Medicine; Medicine & Public Health; Medulloblastoma; Methylation; Microarray Analysis; Multivariate analysis; Neurophysiology; Neurosciences; Original Paper; Pathology; Patients; Phenotypes; Risk; Risk groups; Survival; Wnt protein
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-022-02522-4

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.