Prognostic significance of clinical, histopathological, and molecular characteristics of medulloblastomas in the prospective HIT2000 multicenter clinical trial cohort
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- 作者：Torsten Pietsch (1)
Rene Schmidt (2)
Marc Remke (4)
Andrey Korshunov (5) (6)
Volker Hovestadt (15) (7)
David T. W. Jones (15) (3)
J?rg Felsberg (13) (8)
Kerstin Kaulich (13) (8)
Tobias Goschzik (1)
Marcel Kool (15) (3)
Paul A. Northcott (15) (3)
Katja von Hoff (9)
André O. von Bueren (10) (9)
Carsten Friedrich (9)
Martin Mynarek (9)
Heyko Skladny (11)
Gudrun Fleischhack (12)
Michael D. Taylor (4)
Friedrich Cremer (11)
Peter Lichter (15) (7)
Andreas Faldum (2)
Guido Reifenberger (13) (8)
Stefan Rutkowski (9)
Stefan M. Pfister (14) (15) (3) - 关键词：Medulloblastoma ; Biomarker ; Risk stratification ; Prospective ; Clinical trial cohort ; Methylation profiling
- 刊名：Acta Neuropathologica
- 出版年：2014
- 出版时间：July 2014
- 年：2014
- 卷：128
- 期：1
- 页码：137-149
- 全文大小：
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Rene Schmidt (2)
Marc Remke (4)
Andrey Korshunov (5) (6)
Volker Hovestadt (15) (7)
David T. W. Jones (15) (3)
J?rg Felsberg (13) (8)
Kerstin Kaulich (13) (8)
Tobias Goschzik (1)
Marcel Kool (15) (3)
Paul A. Northcott (15) (3)
Katja von Hoff (9)
André O. von Bueren (10) (9)
Carsten Friedrich (9)
Martin Mynarek (9)
Heyko Skladny (11)
Gudrun Fleischhack (12)
Michael D. Taylor (4)
Friedrich Cremer (11)
Peter Lichter (15) (7)
Andreas Faldum (2)
Guido Reifenberger (13) (8)
Stefan Rutkowski (9)
Stefan M. Pfister (14) (15) (3)
1. Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany
2. Institute of Biostatistics and Clinical Research, WW University of Muenster, Muenster, Germany
4. Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
5. Department of Neuropathology, University of Heidelberg, Heidelberg, Germany
6. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
15. German Cancer Consortium (DKTK), Partner site, Heidelberg, Germany
7. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
3. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
13. German Cancer Consortium (DKTK), Partner site, Essen/Düsseldorf, Germany
8. Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
9. Department of Pediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistra?e 52, 20246, Hamburg, Germany
10. Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center G?ttingen, G?ttingen, Germany
11. Centre for Human Genetics, Mannheim, Germany
12. Division of Pediatric Hematology/Oncology, Pediatrics III, Children’s Hospital of University Essen, Essen, Germany
14. Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany - ISSN：1432-0533
文摘
This study aimed to prospectively evaluate clinical, histopathological and molecular variables for outcome prediction in medulloblastoma patients. Patients from the HIT2000 cooperative clinical trial were prospectively enrolled based on the availability of sufficient tumor material and complete clinical information. This revealed a cohort of 184 patients (median age 7.6?years), which was randomly split at a 2:1 ratio into a training (n?=?127), and a test (n?=?57) dataset in order to build and test a risk score for this population. Independent validation was performed in a non-overlapping cohort (n?=?83). All samples were subjected to thorough histopathological investigation, CTNNB1 mutation analysis, quantitative PCR, MLPA and FISH analyses for cytogenetic variables, and methylome analysis. By univariable analysis, clinical factors (M-stage), histopathological variables (large cell component, endothelial proliferation, synaptophysin pattern), and molecular features (chromosome 6q status, MYC amplification, subgrouping) were found to be prognostic. Molecular consensus subgrouping (WNT, SHH, Group 3, Group 4) was validated as an independent feature to stratify patients into different risk groups. When comparing methods for the identification of WNT-driven medulloblastoma, this study identified CTNNB1 sequencing and methylation profiling to most reliably identify these patients. After removing patients with particularly favorable (CTNNB1 mutation, extensive nodularity) or unfavorable (MYC amplification) markers, a risk score for the remaining “intermediate molecular risk-population dependent on age, M-stage, pattern of synaptophysin expression, and MYCN copy-number status was identified, with speckled synaptophysin expression indicating worse outcome. Test and independent validation of the score confirmed significant discrimination of patients by risk profile. Methylation subgrouping and CTNNB1 mutation status represent robust tools for the risk stratification of medulloblastoma. A simple clinico-pathological risk score was identified, which was confirmed in a test set and by independent clinical validation.