Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma.
OBJECTIVE
Medulloblastoma is the most common malignant brain tumor in children. Despite multimodal aggressive treatment, nearly half of the patients die as a result of this tumor. Identification of molecular markers for prognosis and development of novel pathogenesis-based therapies depends crucially on a better understanding of medulloblastoma pathomechanisms.


METHODS
We performed genome-wide analysis of DNA copy number imbalances in 47 medulloblastomas using comparative genomic hybridization to large insert DNA microarrays (matrix-CGH). The expression of selected candidate genes identified by matrix-CGH was analyzed immunohistochemically on tissue microarrays representing medulloblastomas from 189 clinically well-documented patients. To identify novel prognostic markers, genomic findings and protein expression data were correlated to patient survival.


RESULTS
Matrix-CGH analysis revealed frequent DNA copy number alterations of several novel candidate regions. Among these, gains at 17q23.2-qter (P < .01) and losses at 17p13.1 to 17p13.3 (P = .04) were significantly correlated to poor prognosis. Within 17q23.2-qter and 7q21.2, two of the most frequently gained chromosomal regions, confined amplicons were identified that contained the PPM1D and CDK6 genes, respectively. Immunohistochemistry revealed strong expression of PPM1D in 148 (88%) of 168 and CDK6 in 50 (30%) of 169 medulloblastomas. Overexpression of CDK6 correlated significantly with poor prognosis (P < .01) and represented an independent prognostic marker of overall survival on multivariate analysis (P = .02).


CONCLUSIONS
We identified CDK6 as a novel molecular marker that can be determined by immunohistochemistry on routinely processed tissue specimens and may facilitate the prognostic assessment of medulloblastoma patients. Furthermore, increased protein-levels of PPM1D and CDK6 may link the TP53 and RB1 tumor suppressor pathways to medulloblastoma pathomechanisms.
Mendrzyk
Frank
F
Division of Molecular Genetics (B060), German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
Radlwimmer
Bernhard
B
Joos
Stefan
S
Kokocinski
Felix
F
Benner
Axel
A
Stange
Daniel E
DE
Neben
Kai
K
Fiegler
Heike
H
Carter
Nigel P
NP
Reifenberger
Guido
G
Korshunov
Andrey
A
Lichter
Peter
P
D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D002528:Cerebellar Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D002869:Chromosome Aberrations; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D051361:Cyclin-Dependent Kinase 6 / Q000096:biosynthesis / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008527:Medulloblastoma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis / Q000235:genetics; D011379:Prognosis; D000071636:Protein Phosphatase 2C; D016019:Survival Analysis
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D051361:Cyclin-Dependent Kinase 6; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C