Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci.
OBJECTIVE
Medulloblastoma is the most common malignant brain tumor in children. Current treatment decisions are based on clinical variables. Novel tumor-derived biomarkers may improve the risk stratification of medulloblastoma patients.


METHODS
A model for the molecular risk stratification was proposed from an array-based comparative genomic hybridization (array-CGH) screen (n = 80). Fluorescence in situ hybridization (FISH) analyses for chromosome arms 6q, 17p, and 17q and the MYC and MYCN loci were performed in an independent validation set (n = 260). Copy number aberrations were correlated with clinical, histologic, and survival data.


RESULTS
Gain of 6q and 17q and genomic amplification of MYC or MYCN were each associated with poor outcome in the array-CGH study (n = 80). In contrast, all patients with 6q-deleted tumors survived. Given these findings, the following hierarchical molecular staging system was defined: (1) MYC/MYCN amplification, (2) 6q gain, (3) 17q gain, (4) 6q and 17q balanced, and (5) 6q deletion. The prognostic value of this staging system was investigated by FISH analysis (n = 260). The addition of molecular markers to clinical risk factors resulted in the identification of a large proportion of patients (72 of 260 patients; 30%) at high risk for relapse and death who would be considered standard risk by application of clinical variables alone.


CONCLUSIONS
Genomic aberrations in medulloblastoma are powerful independent markers of disease progression and survival. By adding genomic markers to established clinical and histologic variables, outcome prediction can be substantially improved. Because the analyses can be conducted on routine paraffin-embedded material, it will be especially feasible to use this novel molecular staging system in large multicenter clinical trials.
Pfister
Stefan
S
Division of Molecular Genetics and Biostatistics and Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany. s.pfister@dkfz.de
Remke
Marc
M
Benner
Axel
A
Mendrzyk
Frank
F
Toedt
Grischa
G
Felsberg
Jörg
J
Wittmann
Andrea
A
Devens
Frauke
F
Gerber
Nicolas U
NU
Joos
Stefan
S
Kulozik
Andreas
A
Reifenberger
Guido
G
Rutkowski
Stefan
S
Wiestler
Otmar D
OD
Radlwimmer
Bernhard
B
Scheurlen
Wolfram
W
Lichter
Peter
P
Korshunov
Andrey
A
D019540:Area Under Curve; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D005260:Female; D018628:Gene Dosage; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000401:mortality; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D011379:Prognosis; D012372:ROC Curve; D046888:Tissue Array Analysis
C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins