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000182882 1001_ $$aMynarek, Martin$$b0
000182882 245__ $$aIdentification of low and very high-risk patients with non-WNT/non-SHH medulloblastoma by improved clinico-molecular stratification of the HIT2000 and I-HIT-MED cohorts.
000182882 260__ $$aHeidelberg$$bSpringer$$c2023
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000182882 500__ $$a#LA:B310# / 2023 Jan;145(1):97-112
000182882 520__ $$aMolecular 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.
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000182882 650_7 $$2Other$$aGroup 3/4
000182882 650_7 $$2Other$$aMedulloblastoma
000182882 650_7 $$2Other$$aNon-WNT/non-SHH
000182882 650_7 $$2Other$$aRisk stratification
000182882 7001_ $$aObrecht, Denise$$b1
000182882 7001_ $$0P:(DE-He78)45440b44791309bd4b7dbb4f73333f9b$$aSill, Martin$$b2$$udkfz
000182882 7001_ $$0P:(DE-He78)a46a5b2a871859c8e2d63d2f8c666807$$aSturm, Dominik$$b3$$udkfz
000182882 7001_ $$aKloth-Stachnau, Katja$$b4
000182882 7001_ $$0P:(DE-He78)a23e88cc676489fe05be8c178ceaf58e$$aSelt, Florian$$b5$$udkfz
000182882 7001_ $$0P:(DE-He78)3de637452ba900e2bdd359b8f41953bf$$aEcker, Jonas$$b6$$udkfz
000182882 7001_ $$avon Hoff, Katja$$b7
000182882 7001_ $$aJuhnke, Björn-Ole$$b8
000182882 7001_ $$aGoschzik, Tobias$$b9
000182882 7001_ $$aPietsch, Torsten$$b10
000182882 7001_ $$aBockmayr, Michael$$b11
000182882 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b12$$udkfz
000182882 7001_ $$0P:(DE-He78)a8a10626a848d31e70cfd96a133cc144$$avon Deimling, Andreas$$b13$$udkfz
000182882 7001_ $$0P:(DE-He78)143af26de9d57bf624771616318aaf7c$$aWitt, Olaf$$b14$$udkfz
000182882 7001_ $$aSchüller, Ulrich$$b15
000182882 7001_ $$aBenesch, Martin$$b16
000182882 7001_ $$aGerber, Nicolas U$$b17
000182882 7001_ $$0P:(DE-He78)a1f4b408b9155beb2a8f7cba4d04fe88$$aSahm, Felix$$b18$$udkfz
000182882 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b19$$udkfz
000182882 7001_ $$0P:(DE-He78)8d9c904a6cea14d4c99c78ba46e41f93$$aKorshunov, Andrey$$b20$$udkfz
000182882 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b21$$udkfz
000182882 7001_ $$aRutkowski, Stefan$$b22
000182882 7001_ $$0P:(DE-He78)0be2f86573954f87e97f8a4dbb05cb0f$$aMilde, Till$$b23$$eLast author$$udkfz
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