Predictors of outcome in an AIEOP series of childhood ependymomas: a multifactorial analysis.
Several molecular biomarkers have been suggested as predictors of outcome for pediatric ependymomas but deserve further validation in independent case series. We analyzed intracranial ependymomas belonging to a series of 60 patients prospectively treated according to the protocol sponsored by the Italian Association of Pediatric Hematology-Oncology. We used a tissue microarray to analyze nucleolin (NCL), cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and epidermal growth factor receptor (EGFR) by immunohistochemistry and by 1q gain by fluorescent in situ hybridization. The mRNA expression levels of EGFR, human telomerase reverse-transcriptase (HTERT), and Prominin 1 (PROM 1)/CD133 were evaluated by quantitative real-time PCR from cases with fresh-frozen tumor material available. Univariate and multivariate analyses of updated clinical data confirmed the prognostic significance of surgery (P < .01) and tumor grading (P < .05) for both relapse-free survival (RFS) and overall survival (OS). Among biomolecular markers, HTERT mRNA expression emerged with the strongest association with OS at multivariate analysis (hazard ratio [HR] = 9.9; P = .011); the 5-year OS was 84% versus 48% in the subgroups with HTERT median value <6 versus ≥ 6, respectively (P = .005). Five-year RFS was 46% versus 20% in the subgroups with low versus high NCL protein expression, respectively (P = .004), while multivariate Cox analyses gave suggestively high HRs for high versus low NCL (HR = 1.9; P = .090). The other genes tested were not significant at multivariate analyses, and genetic alterations of CDKN2A, TP53, EGFR, and HTERT loci were rare. The PROM1/CD133 cancer stem cell marker was strongly expressed at both RNA and protein levels in a substantial fraction of cases and was suggestively associated with a more indolent form of the disease. We conclude that NCL and HTERT represent the strongest prognostic biomarkers of RFS and OS, respectively, in our ependymoma case series.
Centro di Riferimento Oncologico, Aviano, Italy. felice.giangaspero@uniroma1.it
Piergiorgio
P
Modena
Francesca R
FR
Buttarelli
Rosalba
R
Miceli
Elena
E
Piccinin
Caterina
C
Baldi
Manila
M
Antonelli
Isabella
I
Morra
Libero
L
Lauriola
Concezio
C
Di Rocco
Maria Luisa
ML
Garrè
Iacopo
I
Sardi
Lorenzo
L
Genitori
Roberta
R
Maestro
Lorenza
L
Gandola
Federica
F
Facchinetti
Paola
P
Collini
Gabriella
G
Sozzi
Felice
F
Giangaspero
Maura
M
Massimino
D000293:Adolescent; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004806:Ependymoma / Q000378:metabolism* / Q000401:mortality; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D010750:Phosphoproteins / Q000032:analysis / Q000096:biosynthesis*; D011379:Prognosis; D016601:RNA-Binding Proteins / Q000032:analysis / Q000096:biosynthesis*; D060888:Real-Time Polymerase Chain Reaction; D019098:Telomerase / Q000032:analysis / Q000096:biosynthesis*; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D000097796:Nucleolin
D014408:Biomarkers, Tumor; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D019098:Telomerase; D000097796:Nucleolin; C509186:TERT protein, human