Identification of tumor-specific molecular signatures in intracranial ependymoma and association with clinical characteristics.
OBJECTIVE
To delineate clinically relevant molecular signatures of intracranial ependymoma.


METHODS
We analyzed 24 primary intracranial ependymomas. For genomic profiling, microarray-based comparative genomic hybridization (CGH) was used and results were validated by fluorescent in situ hybridization and loss of heterozygosity mapping. We performed gene expression profiling using microarrays, real-time quantitative reverse transcriptase polymerase chain reaction, and methylation analysis of selected genes. We applied class comparison analyses to compare both genomic and expression profiling data with clinical characteristics.


RESULTS
A variable number of genomic imbalances were detected by array CGH, revealing multiple regions of recurrent gain (including 2q23, 7p21, 12p, 13q21.1, and 20p12) and loss (including 5q31, 6q26, 7q36, 15q21.1, 16q24, 17p13.3, 19p13.2, and 22q13.3). An ependymoma-specific gene expression signature was characterized by the concurrent abnormal expression of developmental and differentiation pathways, including NOTCH and sonic hedgehog signaling. We identified specific differentially imbalanced genomic clones and gene expression signatures significantly associated with tumor location, patient age at disease onset, and retrospective risk for relapse. Integrated genomic and expression profiling allowed us to identify genes of which the expression is deregulated in intracranial ependymoma, such as overexpression of the putative proto-oncogene YAP1 (located at 11q22) and downregulation of the SULT4A1 gene (at 22q13.3).


CONCLUSIONS
The present exploratory molecular profiling study allowed us to refine previously reported intervals of genomic imbalance, to identify novel restricted regions of gain and loss, and to identify molecular signatures correlating with various clinical variables. Validation of these results on independent data sets represents the next step before translation into the clinical setting.
Modena
Piergiorgio
P
Unit of Molecular Cytogenetics, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy. piergiorgio.modena@istitutotumori.mi.it
Lualdi
Elena
E
Facchinetti
Federica
F
Veltman
Joris
J
Reid
James F
JF
Minardi
Simone
S
Janssen
Irene
I
Giangaspero
Felice
F
Forni
Marco
M
Finocchiaro
Gaetano
G
Genitori
Lorenzo
L
Giordano
Flavio
F
Riccardi
Riccardo
R
Schoenmakers
Eric F P M
EF
Massimino
Maura
M
Sozzi
Gabriella
G
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D015536:Down-Regulation; D004806:Ependymoma / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D019656:Loss of Heterozygosity; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000235:genetics; D000090063:Proto-Oncogene Mas; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015238:Sulfotransferases / Q000235:genetics; D014157:Transcription Factors; D015854:Up-Regulation; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; C000715470:MAS1 protein, human; D010750:Phosphoproteins; D000090063:Proto-Oncogene Mas; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C479953:SULT4A1 protein, human; D015238:Sulfotransferases