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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

Standard

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. / 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.

in: ACTA NEUROPATHOL, Jahrgang 145, Nr. 1, 01.2023, S. 97-112.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Mynarek, M, Obrecht, D, Sill, M, Sturm, D, Kloth-Stachnau, K, Selt, F, Ecker, J, von Hoff, K, Juhnke, B-O, Goschzik, T, Pietsch, T, Bockmayr, M, Kool, M, von Deimling, A, Witt, O, Schüller, U, Benesch, M, Gerber, NU, Sahm, F, Jones, DTW, Korshunov, A, Pfister, SM, Rutkowski, S & Milde, T 2023, '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', ACTA NEUROPATHOL, Jg. 145, Nr. 1, S. 97-112. https://doi.org/10.1007/s00401-022-02522-4

APA

Mynarek, M., Obrecht, D., Sill, M., Sturm, D., Kloth-Stachnau, K., Selt, F., Ecker, J., von Hoff, K., Juhnke, B-O., Goschzik, T., Pietsch, T., Bockmayr, M., Kool, M., von Deimling, A., Witt, O., Schüller, U., Benesch, M., Gerber, N. U., Sahm, F., ... Milde, T. (2023). 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. ACTA NEUROPATHOL, 145(1), 97-112. https://doi.org/10.1007/s00401-022-02522-4

Vancouver

Mynarek M, Obrecht D, Sill M, Sturm D, Kloth-Stachnau K, Selt F et al. 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. ACTA NEUROPATHOL. 2023 Jan;145(1):97-112. https://doi.org/10.1007/s00401-022-02522-4

Bibtex

@article{9d3756028dcb43cfb88dde516bb7c83d,
title = "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",
abstract = "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.",
author = "Martin Mynarek and Denise Obrecht and Martin Sill and Dominik Sturm and Katja Kloth-Stachnau and Florian Selt and Jonas Ecker and {von Hoff}, Katja and Bj{\"o}rn-Ole Juhnke and Tobias Goschzik and Torsten Pietsch and Michael Bockmayr and Marcel Kool and {von Deimling}, Andreas and Olaf Witt and Ulrich Sch{\"u}ller and Martin Benesch and Gerber, {Nicolas U} and Felix Sahm and Jones, {David T W} and Andrey Korshunov and Pfister, {Stefan M} and Stefan Rutkowski and Till Milde",
note = "{\textcopyright} 2022. The Author(s).",
year = "2023",
month = jan,
doi = "10.1007/s00401-022-02522-4",
language = "English",
volume = "145",
pages = "97--112",
journal = "ACTA NEUROPATHOL",
issn = "0001-6322",
publisher = "Springer",
number = "1",

}

RIS

TY - JOUR

T1 - 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

AU - Mynarek, Martin

AU - Obrecht, Denise

AU - Sill, Martin

AU - Sturm, Dominik

AU - Kloth-Stachnau, Katja

AU - Selt, Florian

AU - Ecker, Jonas

AU - von Hoff, Katja

AU - Juhnke, Björn-Ole

AU - Goschzik, Tobias

AU - Pietsch, Torsten

AU - Bockmayr, Michael

AU - Kool, Marcel

AU - von Deimling, Andreas

AU - Witt, Olaf

AU - Schüller, Ulrich

AU - Benesch, Martin

AU - Gerber, Nicolas U

AU - Sahm, Felix

AU - Jones, David T W

AU - Korshunov, Andrey

AU - Pfister, Stefan M

AU - Rutkowski, Stefan

AU - Milde, Till

N1 - © 2022. The Author(s).

PY - 2023/1

Y1 - 2023/1

N2 - 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.

AB - 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.

U2 - 10.1007/s00401-022-02522-4

DO - 10.1007/s00401-022-02522-4

M3 - SCORING: Journal article

C2 - 36459208

VL - 145

SP - 97

EP - 112

JO - ACTA NEUROPATHOL

JF - ACTA NEUROPATHOL

SN - 0001-6322

IS - 1

ER -