Isochromosome 17q is a negative prognostic factor in poor-risk childhood medulloblastoma patients.
BACKGROUND
Medulloblastomas are the most common primary malignant childhood intracranial neoplasms. Patients are currently sorted into three risk groups based on clinical criteria: standard, poor, and infant (<18 months old). We hypothesized that genetic copy number aberrations (CNA) predict prognosis and would provide improved criteria for predicting outcome.


METHODS
DNA from 35 medulloblastoma patients from four Children's Cancer Group trials was analyzed by comparative genomic hybridization to determine CNAs. The genetic alterations were evaluated using statistical and cluster analyses.


RESULTS
The most frequent CNAs were gains on 17q, 7, 1q, and 7q and losses on 17p, 10q, X, 16q, and 11q. Amplification at 5p15.1-p15.3 was also detected. Isochromosome 17q (i(17)(q10)) was associated with poor overall survival (P = 0.03) and event-free survival (P = 0.04) independent of poor risk group classification. Age <3 tended to be associated with <3 CNAs (P = 0.06). Unsupervised cluster analysis sorted the study patients into four subgroups based on CNAs. Supervised analysis using the program Significance Analysis of Microarrays (SAM) quantitatively validated those CNAs identified by unsupervised clustering that significantly distinguished among the four subgroups.


CONCLUSIONS
Medulloblastomas are genetically heterogeneous and can be categorized into separate genetic subgroups by their CNAs using unsupervised cluster analysis and SAM. i(17)(q10) was a significant independent negative prognostic factor. Infant medulloblastomas may be a distinct genetic subset from those of older patients.
Pan
Edward
E
University of California San Francisco, San Francisco, California, USA.
Pellarin
Malgorzata
M
Holmes
Emi
E
Smirnov
Ivan
I
Misra
Anjan
A
Eberhart
Charles G
CG
Burger
Peter C
PC
Biegel
Jaclyn A
JA
Feuerstein
Burt G
BG
D000293:Adolescent; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations / Q000145:classification; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D016000:Cluster Analysis; D005260:Female; D015894:Genome, Human; D006801:Humans; D007223:Infant; D018404:Isochromosomes; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology*; D009693:Nucleic Acid Hybridization / Q000379:methods; D011379:Prognosis; D012307:Risk Factors; D016019:Survival Analysis